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Abstract

Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version “Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)”. The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.

Keywords

cell therapy neurorestoration clinical application guideline neurorestoratology

Introduction

The Chinese Branch of the International Association of Neurorestoratology (IANR) established the first guidelines governing the clinical application of neurorestoration in 2011 (“Chinese Clinical Standard of Neurorestorative Cell Therapy”)¹. These guidelines were revised in 2012 (“Standard Recommendation for the Application of Chinese Clinical Cell Therapy For Neurorestoration”)², in 2015 (“Chinese Clinical Application Guideline of Neurorestorative Cell Therapy)³, and in 2016 (“Clinical Cell Therapy Guidelines for Neurorestoration, China Version 2016”)⁴. The guideline and its revisions have played a significant role in standardizing cell therapy practice in China.

Clinical cell therapies have become increasingly popular around the world. IANR and the Neurorestoratology Professional Committee of the Chinese Medical Doctor Association (Chinese Association of Neurorestoratology [CANR]) collaborated to propose “Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)” based on the Chinese version of the guidelines and approved in principle by the IANR council board members and CANR committee members on September 1, 2016. The document was subsequently edited and literature citations were complemented. The finalized guidelines were then approved by all IANR/CANR members by email communication.

IANR/CANR hopes that these guidelines will be accepted as the applied reference standard for cell therapy of neurological diseases and damage worldwide. In particular, these guidelines may be useful to guide researchers who transplant cells into the brain and spinal cord for therapeutic research purposes. For the detailed protocol and rules of general cell therapies, researchers should first follow the regulations and policies of local governments in their respective countries. Given the rapidly advancing state of the field, the IANR/CANR will amend and update the existing guidelines to reflect the newest results demonstrated in preclinical research, translational studies, and evidence-based clinical studies.

Neurorestoratology is an emerging discipline at the intersection of clinical medicine and neuroscience. Its goal is to restore, promote, and maintain the integrity of impaired or lost neuronal functions and/or structures⁵.

The “Beijing Declaration of IANR” (agreed upon at the IANR 2015 Conference in Tehran) declared as its fundamental tenet that “functional recovery is possible after central nervous system (CNS) injury and neurodegeneration” and noted that “cell therapies may become a key clinical therapeutic option for acute, subacute and/or chronic CNS diseases or damage”⁵. More than 30 types of cells have been identified through preclinical studies as having the capacity for neurorestoration^{6

–66}.

The US Food and Drug Administration (Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products) divided cell therapy products into stem cell–derived cell therapy products and mature/functionally differentiated cell-derived cell therapy products (http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm). Stem cell–derived cell therapy products include embryonic stem cells (ESCs), induced pluripotent stem cells, and adult (multipotent) stem cells. The last one contains neural stem cells (NSCs) and mesenchymal stem cells of different types. Mature/functionally differentiated cell-derived cell therapy products include (1) specialized functional cells such as neural progenitor or precursor cells, olfactory ensheathing cells (OECs), Schwann precursor cells, oligodendroglia precursors, neural-restricted precursors, glial-restricted precursors, neutrophils, neurons, astrocytes, myoblasts, and so on; and (2) nonspecialized functional cells such as bone marrow or umbilical cord blood mononuclear cells, umbilical cord or adipose stromal cells, and fibroblasts and lymphocytes^{63,64,67

–71}. Even though there is some disagreement or controversy concerning the nomenclature of MSCs, so far the majority has accepted the MSC standard criteria made by the International Society for Cellular Therapy to identify MSCs^72,73. While MSCs containing mesenchymal stem cells are able to differentiate into other (adipocytes, chondrocytes, osteocytes, etc.) kinds of cells when cultured in special media for differentiation, this kind of study can be referred to as mesenchymal stem cell research. In those cases, MSCs are cultured for expansion without differentiation; we may refer to this type of study as MSC research. Currently, there remains some misuse of these MSC standard criteria to identify their culturing and expanding MSCs and call them mesenchymal stem cells.

Due to concerns over tumorigenicity and difficulties in controlling differentiation of pluripotent or multipotent stem cells, stem cell–derived cell therapy products require more extensive preclinical and clinical testing. The clinical guidelines presented in this document apply more to mature/functionally differentiated cell therapy. To date, clinical trials of treatments based on those categories of cells have been carried out in over 40 countries with documented safety and functional neurological improvement for patients with CNS diseases and damage^{74

–114}.

Recommended Standards for Personnel and Institutions Conducting Cell Therapies

Equipment

Institutions applying cell therapies to patients must have certified laboratory facilities and equipment that comply with the relevant national standards for ensuring cell quality control (Fig. 1).

Fig. 1.

Recommended standards for personnel and institutions. The standards mainly contain 3 parts: equipment, personal and institutional review board, and ethics committee approval.

Personnel

Clinical personnel

Physicians performing cell transplantation procedures should have documented professional training and certification required to ensure high-level competency in this field. They should have passed all certification examinations recommended by the relevant professional societies or associations.

Laboratory personnel

Directors of cell preparation laboratories should have achieved a high professional rank. Technicians involved in cell preparation should have undergone all relevant professional training and passed all certification examinations in cell preparation recommended by the relevant professional societies or associations.

Oversight personnel

Inspectors assessing cell quality should have undergone all relevant professional training and passed all certification examinations in cell preparation recommended by the relevant professional societies or associations (Fig. 1).

Institutional Review Board and Ethics Committee Approval

All clinical studies or treatment involving cell therapies and human participants must be reviewed and approved by the appropriate institutional review board or ethics committee (Fig. 1).

Provisions

These guidelines include the following provisions: cell type nomenclature, cell quality control, minimal suggested cell doses, patient informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility (Fig. 2).

Fig. 2.

Provisions for cell therapy.

Cell Type Nomenclature

Cells are the basic unit of structure and function of organisms. A stem cell can generate itself in a process known as self-renewal and also produce the other kinds of more differentiated, committed cells with specialized functions. Progenitor or precursor cells are not able to self-renew but instead can multiply rapidly and differentiate into one or more kinds of specialized cells. Mature and functionally differentiated cells usually cannot make additional cells unless they dedifferentiate.

The nomenclature and description of cells used for therapy should specify developmental stage (e.g., embryonic, fetal, neonatal, adult, allogeneic, and autologous), tissue of origin (e.g., blood, bone marrow, umbilical cord blood, placenta, brain, spinal cord, olfactory bulb, subventricular zone, peripheral nerve, adipose, tumor, and cell line), method to isolate or expand the cells (e.g., genetically induced, expanded in culture, laser sorted, minimally manipulated, centrifugation, and type of osmotic gradient), and selection process (e.g., human leukocyte antigen [HLA]- or ABO blood group-matched, CD34⁺, and aldehyde dehydrogenase expressing). If nonhuman, the species must be specified. If mixtures of cells are used, the type of cells should be specified (e.g., mononuclear) together with the approximate percentages of the different types of cells present in the mixture (Fig. 3).

Fig. 3.

Provision for cell type nomenclature. The nomenclature and description of the cells used for therapy should specify species, developmental stage, tissue of origin, method to isolate or expand the cells, and selection process. If mixtures of cells are used, the type of cells should be specified.

Cell Quality Control

Quality control is essential for ensuring safety and efficacy of cell therapies. Quality control encompasses cell collection; culturing; identifying; amplifying; detecting composition and relevant cytokines, genetic or other manipulations, and passage number; exogenous factors; cell storage; assessment of biological effects (dynamics proliferation); cell transportation; preparation before clinical use; surgery and cell transplantation; or other administrative approaches. Use of animal serum such as fetal bovine serum (FBS) is discouraged. If FBS is used, it should be washed or otherwise removed before transplantation. If human sera are used, the source and quality of the serum must be documented.

Sterility of the cell preparation must be rigorously monitored. Because microbiological cultures may take days or even weeks to complete, the sterility of the cell preparation procedure must be carefully assessed and validated, particularly if the cells are transplanted before sterility data are available. If sterility testing reveals that the cells are contaminated with bacteria, fungus, or virus, sensitivity to antibiotics, antivirals, or fungicides should be determined. If the cells come from donor sources where infections are possible, donors should be screened for human immunodeficiency virus, hepatitis B virus, cytomegalovirus, or other prevalent contaminants. In addition, if tissues are stored at room temperature for any length of time, endotoxin levels should be determined. Before cells are frozen and stored, dimethylsulfoxide should be tested. The standards for sterility depend on the type and source of cells and route of administration. For example, administration of cells to skin or eyes may require criteria as stringent as for their administration to the CNS.

Before transplantation, certain minimal information must be obtained concerning the cells. These include the number of nucleated cells, the number or percentage of therapeutically relevant cells, and cell viability. Some information may be obtained after treatment as long as the preparation process is validated and contaminants can be treated with antibiotics, antivirals, or fungicides. The maximum time between preparation and transplantation of cells should be based on evidence¹¹⁵ (Fig. 4).

Fig. 4.

Cell quality control. Quality control is essential for ensuring safety and efficacy of cell therapies from the preparation of cells to cell transplantation. Sterility of the cell preparation must be rigorously monitored.

Minimal Suggested Cell Doses

Cells must be used at an effective dose. Thus, the cell dosage and injection volume must be determined and controlled based on evidence of efficacy and safety. Currently, we recommend that the maximum injection volume of cell suspensions does not exceed 200 μL per injection for brain parenchyma^{79,116
–118}, 25 μL per injection into spinal cord parenchyma^74,75, 10 mL by intrathecal injection into cerebrospinal fluid^119,120, and 10 to 100 mL by intravenous and intra-arterial routes^120

–124. The volume or number of cells being transplanted will be reformulated if further trials show stronger evidence or indicate suitable doses in terms of patient body weight.

Current recommendations for a commonly used single dose of cells are as follows (Table 1):

Table 1.

Minimal Suggested Cell Doses.

Olfactory ensheathing cells and Schwann cells	2–3 × 10⁶	1–2 × 10⁶	2–4 × 10⁶	—
Neural progenitor/precursor cells	5–6 × 10⁶	5–6 × 10⁶	10 × 10⁶ (or lateral ventricle)	—
Mesenchymal stromal cells derived from umbilical cord	5–8 × 10⁶	—	10 × 10⁶	0.5–0.8 × 10⁶/kg
Mononuclear cells derived from cord blood	5–6 × 10⁶	6–7 × 10⁶ (above and below the injury site)	—	1–2 × 10⁶/kg
Mononuclear cells derived from bone marrow	5–6 × 10⁶	—	—	3–9 × 10⁸

Note. Current recommendations of commonly used single dose of different cells, including olfactory ensheathing cells and Schwann cells, neural progenitor/precursor cells, mesenchymal stromal cells derived from umbilical cord, mononuclear cells derived from cord blood, and mononuclear cells derived from bone marrow.

OECs and Schwann cells: 2 to 3 × 10⁶ cells for intrathecal injection, 1 to 2 × 10⁶ cells for intraspinal spinal cord injection, and 2 to 4 × 10⁶ cells for brain parenchymal injection^{74,75,79,118,125}.

Neural progenitor/ precursor cells: 5 to 6 × 10⁶ cells by intrathecal injection, 5 to 6 × 10⁶ cells for spinal cord injection, and 10 × 10⁶ by brain parenchymal injection^118,123,125 or lateral ventricle¹²⁶.

MSCs derived from umbilical cord: 0.5 to 0.8 × 10⁶/kg body weight for intravenous infusion (the dose should be reduced by 1/3 to 1/2 for elderly and frail patients), 5 to 8 × 10⁶ for intrathecal injection, and 10 × 10⁶ for brain parenchymal injection^{127

–134}.

Mononuclear cells derived from cord blood: 1 to 2 × 10⁶/kg body weight by intravenous infusion (the dose should be reduced by 1/3 to 1/2 for elderly and frail patients), 5 to 6 × 10⁶ by intrathecal injection^81,87,90,94, and a total of 6 to 7 × 10⁶ cells injected into spinal cord above and below the injury site¹³⁵.

Mononuclear cells derived from bone marrow: 3 to 9 × 10⁸ by intravenous infusion and 5 to 6 × 10⁶ by intrathecal injection^{84,86,121,122,124,126}.

Patient-Informed Consent

Two types of informed consent must be obtained. The first is from donors or parents who must give consent for the cells to be used to treat other patients. For example, if cells are obtained from aborted fetuses, the parent must understand what the cells will be used for and give informed consent. The second is informed consent of the recipient of the cells. Patients and their families have the right to know all the possible benefits and potential risks of matters related with the cell transplantation and procedures. Physicians should continue to learn and master the latest cell therapy–related knowledge in order to give objective answers and explanations. All participants must complete and sign a consent form that is approved by the appropriate institutional review board or ethical committee before the clinical study or cell therapy is applied.

Indications for Undergoing Cell Therapy

Animal studies suggest that cell therapies may be beneficial for a variety of neurological diseases and injury including neurotraumatic injury, neurodegeneration, ischemic/hypoxic brain injury, demyelination, sensory motor disorders, neuropathic pain, and nerve damage caused by intoxication, physical/chemical factors, immune and infectious, inflammatory, hereditary, congenital or developmental factors, and so on. However, until formal regulatory approval is obtained for use of cell therapies for specific indications, cell therapy must be administered only under the auspices of clinical trials and studies approved by appropriate institutional review boards, ethical committees, and regulatory agencies.

The relevant committees for each type of neurorestorative treatment should document the special indications for each treatment and the disease categories.

Contraindications for Undergoing Cell Therapy

Patients with poor health or dysfunction of major organs may not tolerate surgery or cell therapy procedures. The presence of infections, pressure sores, bleeding tendency, coagulation disorders, and emotional disturbance likewise may introduce undesirable complications. Patients with active neoplastic diseases, hypersensitivity, or pregnancy likewise should be excluded unless the cell therapy is specifically intended for these conditions. Clinicians should consider the likelihood that a high incidence of complications risks creating unnecessarily negative and undesirable issues for cell therapy or transplantation procedures.

Documentation of the Procedure and Therapy

The operative procedures, cell therapy, and outcomes must be rigorously documented. The documented data include anesthesia methods, cell quality and source, surgical procedures, transplantation method and site, cell preparation and dose, treatment timing at different stages, and both short- and long-term outcomes.

More preclinical and clinical treatment studies are needed to establish the best doses and therapeutic routes for different cell therapies and conditions. Randomized double-blind clinical trials are needed to establish and validate the safest and most effective clinical practices^{74,75,79,118,128
–130,136

–139}. Specific sites of transplantation should be compared and assessed. For example, in local brain disorders (trauma or stroke), should the cells be injected into the lesion edge? For nonspecial or diffuse disorders (cerebral palsy, amyotrophic lateral sclerosis), what is the best site to inject cells? Should they be injected into the key points for neural network restoration^75,79? Some experience suggests that these key points are located anterior to the lateral ventricle and 23 to 27 mm from the midline, where the frontal corona radiata and pyramidal tract pass through and represent a nexus where numerous projection fibers, association fibers, and commissural fibers converge. Where is the best place to inject into the spinal cord? Some data suggest that cells should be injected into the spinal cord below and above the injury site, at the junction of normal and damaged tissue. For peripheral nerve disorders, should the cells be injected into the damaged site? For brain or spinal cord injury, when is the optimal time window for cell therapy, which mode of cell transplantation is better and what kind of cells should be selected at different stages? All these questions need to be answered in future clinical studies.

Safety Evaluation

Detailed records must be kept for cell therapy–related adverse events by using standardized terminology such as fever, headache, nausea, vomiting, anorexia, infection, rash, poor wound healing, dyspnea, increased/decreased blood pressure, increased/decreased heart rate, neurological deterioration, cerebrospinal fluid leakage, twitch, and so on. In the case of mortality, autopsies should be carried out to determine the cause of death and disposition of the transplanted cells.

Efficacy Evaluation

Efficacy of cell therapies should be evaluated by validated and established standards or scales currently used in the international community to assess the patients’ functions for different diseases (referred to as neurorestoratology¹³⁸ or CNS neurorestoratology¹³⁹). Many organizations, including IANR, regularly hold training courses for physicians to learn specific standards and assessments of patients, to test and evaluate proficiency and consistency, such as volitional control which is evaluated by a motor task involving single and multijoint movement performed repetitively at the same rate and amplitude and provide professional certification. Independent third-party examiners are recommended for clinical trials. Randomized double-blind controlled trials are preferred and required for regulatory approval. Whenever possible, detailed imaging information should be obtained before and after therapy, including magnetic resonance imaging (MRI) scans, such as functional MRI, and diffusion tensor MRI and electrophysiological examination such as transcranial magnetic stimulation (TMS), evoked potential (EP), and electromyogram (EMG) to document the presence of the cells or therapeutic effects. Patients should be scheduled for long-term follow-up examinations to determine whether beneficial effects are lasting. Functional and quality-of-life scales should be used to assess the impact of treatment effects. Natural recovery can occur over a period of time before it stops. This time may differ in different pathological conditions. It is therefore important to record the time elapsed between the pathological event and the intervention and to document other previous treatments (surgical, medical, or pharmacological) and the time prior to the cellular intervention.

Policy of Repeated Treatments

Repeated cell therapies should be based on convincing evidence of efficacy. In the absence of such evidence, patients should not be told that repeated transplants are more effective. If such evidence is not available, clinicians should do randomized trials to obtain such evidence. For example, one possible approach is to use a randomized crossover trial design, where patients are randomized to early or late repeated therapy. To rule out potential placebo effects, some trials should involve sham transplant procedures.

Do Not Charge Patients for Unproven Therapies

There should be agreement within the treatment community that if clinical trials do not show convincing evidence of benefit, practice of the therapy should be discontinued. Patients should not pay for experimental therapies. While there may be differing standards for proof of safety and efficacy, charging patients for unproven cell therapies without regulatory approval is not only illegal but may give cell therapy a bad reputation with regulatory agencies and delay acceptance of cell therapy by the mainstream clinical community. Approved medical treatments including cell therapies will not be fit for this agreement. Many countries and areas such as the United States, India, and Europe¹⁴⁰, however, are adopting the practice of allowing compassionate use of therapies shown to be safe and with some evidence of efficacy to treat disorders for which there is no known effective therapy. Regulatory agencies will often negotiate with the clinician or company for the patient to pay the cost of the therapy.

Basic Principles of Cell Therapy

A number of clinical studies concerning cell therapies with a positive outcome have led to the suggestion that combination cell therapies and/or certain transplantation approaches with rehabilitation can be more effective^{107,123,128
–130,136,138

–200}. IANR/CANR will evaluate such data and actively organize multicenter studies to test these practices for different cells and diseases. Randomized, double-blind, and controlled clinical studies should be carried out, if at all possible.

Publishing Responsibility

All groups that practice clinical cell therapies must promptly analyze and publish their data in peer-reviewed journals, so that other physicians can have access to the information.

Summary

Clinical cell therapies for neurological diseases and damage have shown promise for functional neurorestoration. These guidelines will help to promote the development of clinical cell therapies. Although currently multiple cell types have being used or have continued use for neurorestoration^201,202, additional studies are necessary to determine the best type, doses, route, and timing window for administration. Further investigations in human patients will enhance our comprehension of this up-and-coming treatment.

Footnotes

Authors’ Note

This manuscript was approved by the International Association of Neurorestoratology and Chinese Association of Neurorestoratology.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Paul R. Sanberg is Co-Editor-in-Chief of Cell Transplantation. Neither Paul R. Sanberg nor any of his colleagues were involved in the peer review or decision making processes for this manuscript.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Chinese Branch of International Association of Neurorestoratology and Preparatory Committee of Chinese Association of Neurorestoratology. Chinese clinical standard of neurorestorative cell therapy (2011 first vision). Chin J Clin Physicians. 2011;5(19):5710–5714.

Chinese Branch of the International Association of Neurorestoratology and Preparatory Committee of Chinese Association of Neurorestoratology. Standard recommendation for the application of Chinese clinical cell therapy for neurorestoration. Cell Transplant. 2013;22(Suppl 1):S5–S10.

Chinese Association of Neurorestoratology and Chinese Branch of International Association of Neurorestoratology. Clinical application guideline of neurorestorative cell therapy in China (2015 version). Chin J Cell Stem Cell. 2016;6(1):1–7.

Huang

Chen

Zou

Han

Sun

Mao

. Clinical cell therapy guidelines for neurorestoration (China version 2016). J Neurorestoratology. 2017;5:39–46.

Young

AlZoubi

Saberi

Sharma

Muresanu

Feng

Chen

Huang

. Beijing declaration of International Association of Neurorestoratology (IANR). J Neurorestoratology. 2015;3:121–122.

Döbrössy

Busse

Piroth

Rosser

Dunnett

Nikkhah

. Neurorehabilitation with neural transplantation. Neurorehabil Neural Repair. 2010;24(8):692–701.

Ghanizadeh

. Non-neuronal cell transplantation as a possible therapeutic approach for epilepsy treatment. Brain Res Bull. 2010;83(5):194–195.

Waldau

Hattiangady

Kuruba

Shetty

. Medial ganglionic eminence–derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe epilepsy. Stem Cells. 2010;28(7):1153–1164.

Huang

Chen

Sanberg

. Cell therapy from bench to bedside translation in CNS neurorestoratology era. Cell Med. 2010;1(1):15–46.

10.

Choi

Chung

Yoo

Hwang

Yoo

Lee

Yan

Ahn

Youn

Won

. Cell proliferation and neuroblast differentiation in the rat dentate gyrus after intrathecal treatment with adipose-derived mesenchymal stem cells. Cell Mol Neurobiol. 2011;31(8):1271–1280.

11.

Lopatina

Kalinina

Karagyaur

Stambolsky

Rubina

Revischin

Pavlova

Parfyonova

Tkachuk

. Adipose-derived stem cells stimulate regeneration of peripheral nerves: BDNF secreted by these cells promotes nerve healing and axon growth de novo. PLoS One. 2011;6(3):e17899.

12.

Ikegame

Yamashita

Hayashi

Mizuno

Tawada

You

Yamada

Tanaka

Egashira

Nakashima

Yoshimura

Iwama

. Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy. 2011;13(6):675–685.

13.

Yang

Liu

Shen

Lin

Chiao

Cheng

. Transplantation of adipose tissue-derived stem cells for treatment of focal cerebral ischemia. Curr Neurovasc Res. 2011;8(1):1–13.

14.

Yalvac

Rizvanov

Kilic

Sahin

Mukhamedyarov

Islamov

Palotás

. Potential role of dental stem cells in the cellular therapy of cerebral ischemia. Curr Pharm Des. 2009;15(33):3908–3916.

15.

Dell’Anno

Caiazzo

Leo

Dvoretskova

Medrihan

Colasante

Giannelli

Theka

Russo

Mus

Pezzoli

Gainetdinov

Benfenati

Taverna

Dityatev

Broccoli

. Remote control of induced dopaminergic neurons in parkinsonian rats. J Clin Invest. 2014;124(7):3215–3229.

16.

Dyson

Barker

. Cell–based therapies for Parkinson’s disease. Expert Rev Neurother. 2011;11(6):831–844.

17.

Lasala

Minguell

. Vascular disease and stem cell therapies. Br Med Bull. 2011;98:187–197.

18.

Rhee

Chang

Kim

Shim

Kim

Lee

Suh

Park

Koh

Lee

Lanza

Kim

Lee

. Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease. J Clin Invest. 2011;121(6):2326–2335.

19.

Hunt

. Cryopreservation of human stem cells for clinical application: a review. Transfus Med Hemother. 2011;38(2):107–123.

20.

Zhang

Wang

Chen

Yang

Zhang

Cao

. Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart. PLoS One. 2011;6(4):e19012.

21.

Tomaskovic-Crook

Crook

. Human embryonic stem cell therapies for neurodegenerative diseases. CNS Neurol Disord Drug Targets. 2011;10(4):440–448.

22.

Hernándeza

Torres-Espína

Navarro

. Adult stem cell transplants for spinal cord injury repair: current state in preclinical research. Curr Stem Cell Res Ther. 2011;6(3):273–287.

23.

Loewenbrück

Storch

. Stem cell-based therapies in Parkinson’s disease: future hope or current treatment option? J Neurol. 2011;258(Suppl 2):S346–S353.

24.

Lunn

Sakowski

Federici

Glass

Boulis

Feldman

. Stem cell technology for the study and treatment of motor neuron diseases. Regen Med. 2011;6(2):201–213.

25.

Hilfiker

Kasper

Hass

Haverich

. Mesenchymal stem cells and progenitor cells in connective tissue engineering and regenerative medicine: is there a future for transplantation? Langenbecks Arch Surg. 2011;396(4):489–497.

26.

Gaspard

Vanderhaeghen

. From stem cells to neural networks: recent advances and perspectives for neurodevelopmental disorders. Dev Med Child Neurol. 2011;53(1):13–17.

27.

Pellegrini

Beilharz

. The survival of myoblasts after intramuscular transplantation is improved when fewer cells are injected. Transplantation. 2011;91(5):522–526.

28.

Chang

Chen

Chiang

Chen

Tseng

Soong

Lee

. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. J Biomed Sci. 2011;18(1):54.

29.

Yalvaç

Yarat

Mercan

Rizvanov

Palotás

Şahin

. Characterization of the secretome of human tooth germ stem cells (hTGSCs) reveals neuro-protection by fine-tuning micro–environment. Brain Behav Immun. 2013;32:122–130.

30.

Amoh

Katsuoka

Hoffman

. Multipotent hair follicle stem cells promote repair of spinal cord injury and recovery of walking function. Cell Cycle. 2008;7(12):1865–1869.

31.

Lee

Bae

Jin

. Intracerebellar transplantation of neural stem cells into mice with neurodegeneration improves neuronal networks with functional synaptic transmission. J Vet Med Sci. 2010;72(8):999–1009.

32.

Sotelo

Alvarado-Mallart

. Reconstruction of the defective cerebellar circuitry in adult Purkinje cell degeneration mutant mice by Purkinje cell replacement through transplantation of solid embryonic implants. Neuroscience. 1987;20(1):1–22.

33.

Novikova

Lobov

Wiberg

Novikov

. Efficacy of olfactory ensheathing cells to support regeneration after spinal cord injury is influenced by method of culture preparation. Exp Neurol. 2011;229(1):132–142.

34.

Wan

Dong

. Autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Int J Hematol. 2006;84(3):276–281.

35.

Yarygin

Kholodenko

Konieva

Burunova

Tairova

Gubsky

Cheglakov

Pirogov

Yarygin

Skvortsova

. Mechanisms of positive effects of transplantation of human placental mesenchymal stem cells on recovery of rats after experimental ischemic stroke. Bull Exp Biol Med. 2009;148(6):862–868.

36.

Loftis

. Sertoli cell therapy: a novel possible treatment strategy for treatment–resistant major depressive disorder. Med Hypotheses. 2011;77(1):35–42.

37.

Caiazzo

Dell’Anno

Dvoretskova

Lazarevic

Taverna

Leo

Sotnikova

Menegon

Roncaglia

Colciago

Russo

Carninci

Pezzoli

Gainetdinov

Gustincich

Dityatev

Broccoli

. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature. 2011;476(7359):224–227.

38.

Geremia

Bao

Pniak

Rossoni

Brown

. Schwann cell co-culture improves the therapeutic effect of bone marrow stromal cells on recovery in spinal cord-injured mice. Cell Transplant. 2010;20(7):1065–1086.

39.

Schwartz

. “Tissue-repairing” blood-derived macrophages are essential for healing of the injured spinal cord: from skin-activated macrophages to infiltrating blood-derived cells? Brain Behav Immun. 2010;24(7):1054–1057.

40.

Vaquero

Zurita

. Functional recovery after severe CNS trauma: current perspectives for cell therapy with bone marrow stromal cells. Prog Neurobiol. 2010;93(3):341–349.

41.

Roshal

Tzyb

Pavlova

Soushkevitch

Semenova

Javoronkov

Kolganova

Konoplyannikov

Shevchuk

Yujakov

Karaseva

Ivanova

Chernyshova

Konoplyannikova

Bandurko

Marey

Sukhikh

. Effect of cell therapy on recovery of cognitive functions in rats during the delayed period after brain injury. Bull Exp Biol Med. 2009;148(1):140–147.

42.

Lin

Shih

Lin

Hsiao

Hsu

. Human umbilical mesenchymal stem cells promote recovery after ischemic stroke. Stroke. 2011;42(7):2045–2053.

43.

Chehrehasa

Windus

Ekberg

Scott

Amaya

Mackay-Sim

St John

. Olfactory glia enhance neonatal axon regeneration. Mol Cell Neurosci. 2010;45(3):277–288.

44.

Bonner

Connors

Silverman

Kowalski

Lemay

Fischer

. Grafted neural progenitors integrate and restore synaptic connectivity across the injured spinal cord. J Neurosci. 2011;31(12):4675–4686.

45.

Nagai

Kawao

Okada

Okumoto

Teramura

Ueshima

Umemura

Matsuo

. Systemic transplantation of embryonic stem cells accelerates brain lesion decrease and angiogenesis. Neuroreport. 2010;21(8):575–579.

46.

Ronaghi

Erceg

Moreno-Manzano

Stojkovic

. Challenges of stem cell therapy for spinal cord injury: human embryonic stem cells, endogenous neural stem cells, or induced pluripotent stem cells? Stem Cells. 2010;28(1):93–99.

47.

Salehi

Pasbakhsh

Soleimani

Abbasi

Hasanzadeh

Modaresi

Sobhani

. Repair of spinal cord injury by co-transplantation of embryonic stem cell-derived motor neuron and olfactory ensheathing cell. Iran Biomed J. 2009;13(3):125–135.

48.

Park

Kang

Byun

Lee

Maeng

Rho

. Peripheral nerve regeneration using autologous porcine skin-derived mesenchymal stem cells. J Tissue Eng Regen Med. 2012;6(2):113–124.

49.

Rosenkranz

Meier

. Umbilical cord blood cell transplantation after brain ischemia—from recovery of function to cellular mechanisms. Ann Anat. 2011;193(4):371–379.

50.

Xiong

Cao

Zhang

Huang

Chen

Zhang

Jia

Xiong

Liang

Sun

Lin

Wang

. Long-term efficacy and safety of human umbilical cord mesenchymal stromal cells in rotenone-induced hemiparkinsonian rats. Biol Blood Marrow Transplant. 2010;16(11):1519–1529.

51.

Dongmei

Jing

Mei

Ling

Hongmin

Zhidong

Zikuan

Hengxiang

. Clinical analysis of the treatment of spinocerebellar ataxia and multiple system atrophy-cerebellar type with umbilical cord mesenchymal stromal cells. Cytotherapy. 2011;13(8):913–917.

52.

Wang

Piao

Larsen

Kondo

Duncan

. Migration and remyelination by oligodendrocyte progenitor cells transplanted adjacent to focal areas of spinal cord inflammation. J Neurosci Res. 2011;89(11):1737–1746.

53.

Shao

Liu

Zhang

Gao

. Effects of tanycytes transplantation on the motor function score and rubrospinal motor evoked potentials of adult rats after spinal cord completely transected. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2010;26(4):433–435.

54.

Michel-Monigadon

Brachet

Neveu

Naveilhan

. Immunoregulatory properties of neural stem cells. Immunotherapy. 2011;3(Suppl 4):39–41.

55.

Obenaus

Dilmac

Tone

Tian

Hartman

Digicaylioglu

Snyder

Ashwal

. Long-term magnetic resonance imaging of stem cells in neonatal ischemic injury. Ann Neurol. 2011;69(2):282–291.

56.

Eaton

Widerström-Noga

Wolfe

. Subarachnoid transplant of the human neuronal hNT2.19 serotonergic cell line attenuates behavioral hypersensitivity without affecting motor dysfunction after severe contusive spinal cord injury. Neurol Res Int. 2011;2011:891605.

57.

Minnerup

Kim

Schmidt

Diederich

Bauer

Schilling

Strecker

Ringelstein

Sommer

Schöler

Schäbitz

. Effects of neural progenitor cells on sensorimotor recovery and endogenous repair mechanisms after photothrombotic stroke. Stroke. 2011;42(6):1757–1763.

58.

Wang

Zhang

Guo

Shen

Shang

Chen

Yao

Yin

Tian

. In-vivo PET imaging of implanted human retinal pigment epithelium cells in a Parkinson’s disease rat model. Nucl Med Commun. 2008;29(5):455–461.

59.

Narantuya

Nagai

Sheikh

Wakabayashi

Shiota

Watanabe

Masuda

Kobayashi

Kim

Yamaguchi

. Microglia transplantation attenuates white matter injury in rat chronic ischemia model via matrix metalloproteinase-2 inhibition. Brain Res. 2010;1316:145–152.

60.

Davies

Shih

Noble

Mayer-Proschel

Davies

Proschel

. Transplantation of specific human astrocytes promotes functional recovery after spinal cord injury. PLoS One. 2011;6(3):e17328.

61.

Yang

Song

Liu

Xue

Hui

. An experimental study on intracerebroventricular transplantation of human amniotic epithelial cells in a rat model of Parkinson’s disease. Neurol Res. 2010;32(10):1054–1059.

62.

Cipriani

Bonini

Marchina

Balgkouranidou

Caimi

Grassi Zucconi

Barlati

. Mesenchymal cells from human amniotic fluid survive and migrate after transplantation into adult rat brain. Cell Biol Int. 2007;31(8):845–850.

63.

Huang

Chen

. Questions and discussion of clinical cell therapy in Neurorestoratology. Chin J Cell Stem Cell. 2012;2(3):154–159.

64.

Huang

Mao

Chen

Liu

. Progress and challenges with clinical cell therapy in neurorestoratology. J Neurorestoratology. 2015;3:91–95.

65.

Buzanska

Jurga

Stachowiak

Domanska-Janik

. Neural stem-like cell line derived from a nonhematopoietic population of human umbilical cord blood. Stem Cells Dev. 2006;15(3):391–406.

66.

Janowski

Lukomska

Domanska-Janik

. Migratory capabilities of human umbilical cord blood-derived neural stem cells (HUCB–NSC) in vitro. Acta Neurobiol Exp. 2011;71(1):24–35.

67.

Vertès

. 2010 world stem cell summit—part 2. IDrugs. 2010;13(12):822–824.

68.

Schwarz

. Translation of stem cell therapy for neurological diseases. Transl Res. 2010;156(3):155–160.

69.

Baker

. Stem-cell pioneer bows out. Nature. 2011;479(7374):459.

70.

Reardon

Cyranoski

. Japan stem-cell trial stirs envy. Nature. 2014;513(7518):287–288.

71.

Brown

Levi

Lequeux

Wong

Mojallal

Longaker

. Basic science review on adipose tissue for clinicians. Plast Reconstr Surg. 2010;126(6):1936–1946.

72.

Dominici

Le Blanc

Mueller

Slaper-Cortenbach

Marini

Krause

Deans

Keating

Prockop

Horwitz

. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317.

73.

Galipeau

Krampera

Barrett

Dazzi

Deans

DeBruijn

Dominici

Fibbe

Gee

Gimble

Hematti

Koh

LeBlanc

Martin

McNiece

Mendicino

Ortiz

Phinney

Planat

Shi

Stroncek

. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy. 2016;18(2):151–159.

74.

Huang

Chen

Wang

Xiu

Wang

Zhang

Song

Hao

Pang

Sun

. Influence of patients’ age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury. Chin Med J. 2003;116(10):1488–1491.

75.

Huang

Chen

Wang

Zhang

Liu

. Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: a controlled pilot study. Clin Transplant. 2008;22(60):710–718.

76.

Raisman

Carlstedt

Choi

. Clinical prospects for transplantation of OECs in the repair of brachial and lumbosacral plexus injuries: opening a door. Exp Neurol. 2011;229(1):168–173.

77.

Lima

Escada

Pratas-Vital

Branco

Arcangeli

Lazzeri

Maia

Capucho

Hasse-Ferreira

Peduzzi

. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil Neural Repair. 2010;24(1):10–22.

78.

Mackay-Sim

Féron

Cochrane

Bassingthwaighte

Bayliss

Davies

Fronek

Gray

Kerr

Licina

Nowitzke

Perry

Silburn

Urquhart

Geraghty

. Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain. 2008;131(Pt 9):2376–2386.

79.

Chen

Huang

Xie

Liu

Jiang

Zhang

Liu

Chen

Wang

Ren

Zhou

. Intracranial transplant of olfactory ensheathing cells in children and adolescents with cerebral palsy: a randomized controlled clinical trial. Cell Transplant. 2010;19(2):185–191.

80.

Mizuno

. Adipose-derived stem and stromal cells for cell-based therapy: current status of preclinical studies and clinical trials. Curr Opin Mol Ther. 2010;12(4):442–449.

81.

Sanberg

Eve

Willing

Garbuzova-Davis

Tan

Sanberg

Allickson

Cruz

Borlongan

. The treatment of neurodegenerative disorders using umbilical cord blood and menstrual blood-derived stem cells. Cell Transplant. 2011;20(1):85–94.

82.

Richardson

Freed

Shimamoto

Starr

. Pallidal neuronal discharge in Parkinson’s disease following intraputamenal fetal mesencephalic allograft. J Neurol Neurosurg Psychiatry. 2011;82(3):266–271.

83.

Mendez

Dagher

Hong

Gaudet

Weerasinghe

McAlister

King

Desrosiers

Darvesh

Acorn

Robertson

. Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases. J Neurosurg. 2002;96(3):589–596.

84.

Liao

Harting

Hetz

Walker

Shah

Corkins

Hughes

Jimenez

Kosmach

Day

Tsao

Lee

Worth

Baumgartner

Cox

Jr . Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children. Pediatr Crit Care Med. 2015;16(3):245–255.

85.

Walker

Harting

Shah

Day

El Khoury

Savitz

Baumgartner

Cox

. Progenitor cell therapy for the treatment of central nervous system injury: a review of the state of current clinical trials. Stem Cells Int. 2010;2010:369578.

86.

Karussis

Karageorgiou

Vaknin-Dembinsky

Gowda-Kurkalli

Gomori

Kassis

Bulte

Petrou

Ben-Hur

Abramsky

Slavin

. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67(10):1187–1194.

87.

Attar

Ayten

Ozdemir

Ozgencil

Bozkurt

Kaptanoglu

Beksac

Kanpolat

. An attempt to treat patients who have injured spinal cords with intralesional implantation of concentrated autologous bone marrow cells. Cytotherapy. 2011;13(1):54–60.

88.

Freedman

Bar-Or

Atkins

Karussis

Frassoni

Lazarus

Scolding

Slavin

Le Blanc

Uccelli

; MSCT Study Group. The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis: consensus report of the International MSCT Study Group. Mult Scler. 2010;16(4):503–510.

89.

Forthofer

Wirth

ED III

. Coordination of a neural tissue transplantation study in patients with posttraumatic syringomyelia. SCI Nurs. 2001;18(1):19–29.

90.

Yang

Zhang

Cho

Shu

Sheng

Zhao

Tang

Jiang

Gandjian

Ichim

. Human umbilical cord blood-derived mononuclear cell transplantation: case series of 30 subjects with hereditary ataxia. J Transl Med. 2011;9:65.

91.

López-Lozano

Bravo

Brera

Dargallo

Salmeán

Uría

Insausti

Millán

. Long-term follow-up in 10 Parkinson’s disease patients subjected to fetal brain grafting into a cavity in the caudate nucleus: the Clinica Puerta de Hierro experience. CPH Neural Transplantation Group. Transplant Proc. 1995;27(1):1395–1400.

92.

Appel

Engelhardt

Henkel

Siklos

Beers

Yen

Simpson

Luo

Carrum

Heslop

Brenner

Popat

. Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis. Neurology. 2008;71(17):1326–1334.

93.

Sharma

Gokulchandran

Sane

Gokulchandran

Sane

Badhe

Kulkarni

Lohia

Nagrajan

Thomas

. Detailed analysis of the clinical effects of cell therapy for thoracolumbar spinal cord injury: an original study. J Neurorestoratology. 2013;1:13–22.

94.

Gong

Wang

Yang

Han

. Human umbilical cord blood mononuclear cell transplantation for delayed encephalopathy after carbon monoxide intoxication. J Neurorestoratology. 2013;1:23–29.

95.

Sych

Klunnik

Ivankova

Matyaschuk

Demchuk

Novytska

Arkhipenko

Shalita

Siniscalco

. Efficacy of fetal stem cells in Duchenne muscular dystrophy therapy. J Neurorestoratology. 2014;2:37–46.

96.

Tsolaki

Zygouris

Tsoutsikas

Anestakis

Koliakos

. Treatment with adipose stem cells in a patient with moderate Alzheimer’s disease: case report. J Neurorestoratology. 2015;3:115–120.

97.

Huang

Sun

Chen

Moviglia

Chernykh

von Wild

Deda

Kang

Kumar

Jeon

Zhang

Brunelli

Bohbot

Soler

Cristante

Onose

Kern

Carraro

Saberi

Sharma

. Consensus of clinical neurorestorative progress in patients with complete chronic spinal cord injury. Cell Transplant. 2014;23(Suppl 1):S5–S17.

98.

Qiao

Huang

Muresanu

. Clinical neurorestorative progress in Alzheimer’s disease. J Neurorestoratology. 2015;3:1–9.

99.

Huang

Chen

Huang

. Clinical neurorestorative progress in traumatic brain injury. J Neurorestoratology. 2015;3:57–62.

100.

Qiao

Huang

. Clinical neurorestorative progress in stroke. J Neurorestoratology. 2015;3:63–71.

101.

Geng

Mark

. Clinical neurorestorative progress in multiple sclerosis. J Neurorestoratology. 2015;3:83–90.

102.

Chen

Huang

Duan

Mao

. Clinical neurorestorative progress in Parkinson’s disease. J Neurorestoratology. 2015;3:101–107.

103.

Chen

Huang

Mao

. Clinical neurorestorative progress in amyotrophic lateral sclerosis. J Neurorestoratology. 2015;3:109–114.

104.

Sharma

Geng

Sane

Kulkarni

. Clinical neurorestorative progresses in cerebral palsy. J Neurorestoratology. 2017;5:51–57.

105.

Moviglia

Varela

Brizuela

Moviglia Brandolino

Farina

Etchegaray

Piccone

Hirsch

Martinez

Marino

Deffain

Coria

Gonzáles

Sztanko

Salas–Zamora

Previgliano

Aingel

Farias

Gaeta

Saslavsky

Blasseti

. Case report on the clinical results of a combined cellular therapy for chronic spinal cord injured patients. Spinal Cord. 2009;47(6):499–503.

106.

Moviglia

Moviglia-Brandolino

Varela

Albanese

Piccone

Echegaray

Martinez

Blasseti

Farias

Farina

Perusso

Gaeta

. Feasibility, safety, and preliminary proof of principles of autologous neural stem cell treatment combined with T-cell vaccination for ALS patients. Cell Transplant. 2012;21(Suppl 1):S57–S63.

107.

Huang

Chen

Zhang

Liu

. Long-term outcome of olfactory ensheathing cell therapy for patients with complete chronic spinal cord injury. Cell Transplant. 2012;21(Suppl 1):S23–S31.

108.

Tabakow

Jarmundowicz

Czapiga

Fortuna

Miedzybrodzki

Czyz

Huber

Szarek

Okurowski

Szewczyk

Gorski

Raisman

. Transplantation of autologous olfactory ensheathing cells in complete human spinal cord injury. Cell Transplant. 2013;22(9):1591–1612.

109.

Tabakow

Raisman

Fortuna

Czyz

Huber

Szewczyk

Okurowski

Miedzybrodzki

Czapiga

Salomon

Halon

Lipiec

Kulczyk

Jarmundowicz

. Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging. Cell Transplant. 2014;23(12):1631–1655.

110.

Riley

Glass

Feldman

Polak

Bordeau

Federici

Johe

Boulis

. Intraspinal Stem Cell Transplantation in ALS: a phase I trial, cervical microinjection and final surgical safety outcomes. Neurosurgery. 2012;71(2):405–416.

111.

Feldman

Boulis

Hur

Johe

Rutkove

Federici

Polak

Bordeau

Sakowski

Glass

. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol. 2014;75(3):363–373.

112.

Mazzini

Ferrero

Luparello

Rustichelli

Gunetti

Mareschi

Testa

Stecco

Tarletti

Miglioretti

Fava

Nasuelli

Cisari

Massara

Vercelli

Oggioni

Carriero

Cantello

Monaco

Fagioli

. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a phase I clinical trial. Exp Neurol. 2010;223(1):229–237.

113.

Mazzini

Gelati

Profico

Sgaravizzi

Projetti Pensi

Muzi

Ricciolini

Rota Nodari

Carletti

Giorgi

Spera

Domenico

Bersano

Petruzzelli

Cisari

Maglione

Sarnelli

Stecco

Querin

Masiero

Cantello

Ferrari

. Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med. 2015;13:17.

114.

Seledtsova

Rabinovich

Belogorodtsev

Parlyuk

Seledtsov

Kozlov

. Delayed results of transplantation of fetal neurogenic tissue in patients with consequences of spinal cord trauma. Bull Exp Biol Med. 2010;149(4):530–533.

115.

Gobbel

Kondziolka

Fellows-Mayle

Uram

. Cellular transplantation for the nervous system: impact of time after preparation on cell viability and survival. J Neurosurg. 2010;113(3):666–672.

116.

Savitz

Dinsmore

Henderson

Stieg

Caplan

. Neurotransplantation of fetal porcine cells in patients with basal ganglia infarcts: a preliminary safety and feasibility study. Cerebrovasc Dis. 2005;20(2):101–107.

117.

Nelson

Kondziolka

Wechsler

Goldstein

Gebel

DeCesare

Elder

Zhang

Jacobs

McGrogan

Lee

Trojanowski

. Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. Am J Pathol. 2002;160(4):1201–1206.

118.

Huang

Chen

Wang

Zhang

Liu

Zhang

. Olfactory ensheathing cells transplantation for central nervous system diseases in 1,255 patients. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2009;23(1):14–20.

119.

Syková

Rychmach

Drahorádová

Konrádová

Růžičková

Voříšek

Forostyak

Homola

Bojar

. Transplantation of mesenchymal stromal cells in patients with amyotrophic lateral sclerosis: results of phase I/IIa clinical trial. Cell Transplant. 2017;26(4):647–658.

120.

Mehta

Feroz

Thakkar

Vanikar

Shah

Trivedi

. Subarachnoid placement of stem cells in neurological disorders. Transplant Proc. 2008;40(4):1145–1147.

121.

Battistella

de Freitas

da Fonseca

Mercante

Gutfilen

Goldenberg

Dias

Kasai-Brunswick

Wajnberg

Rosado-de-Castro

Alves-Leon

Mendez-Otero

Andre

. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen Med. 2011;6(1):45–52.

122.

Friedrich

Martins

Araújo

Klamt

Vedolin

Garicochea

Raupp

Sartori El Ammar

Machado

Costa

Nogueira

Rosado-de-Castro

Mendez-Otero

Freitas

. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 2012;21(Suppl 1):S13–S21.

123.

Moviglia

Fernandez Viña

Brizuela

Saslavsky

Vrsalovic

Varela

Bastos

Farina

Etchegaray

Barbieri

Martinez

Picasso

Schmidt

Brizuela

Gaeta

Costanzo

Moviglia Brandolino

Merino

Pes

Veloso

Rugilo

. Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy. 2006;8(3):202–209.

124.

Lee

Hong

Moon

Lee

Ahn

Bang

; STARTING collaborators. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem cells. 2010;28(6):1099–1106.

125.

Chen

Huang

Jiang

Wang

Bao

Wang

. Electromyogram evaluation in 389 patients with amyotrophic lateral sclerosis following olfactory ensheathing cell intracranial transplantation. J Clin Rehabil Tissue Eng Res. 2008;12(43):8422–8425.

126.

Luan

Liu

Wang

Yang

Wang

Gong

. Effects of neural progenitor cell transplantation in children with severe cerebral palsy. Cell Transplant. 2012;21(Suppl 1):S91–S98.

127.

Bang

Lee

. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874–882.

128.

Chen

Huang

Zhang

Liu

Chen

Xiao

. Multiple cell transplantation based on an intraparenchymal approach for patients with chronic phase stroke. Cell Transplant. 2013;22 (Suppl 1):S83–S91.

129.

Chen

Huang

Zhang

Liu

Chen

Xiao

. Preliminary report of multiple cell therapy for patients with multiple system atrophy. Cell Transplant. 2013;22(Suppl 1):S93–S99.

130.

Chen

Huang

Zhang

Liu

Chen

Xiao

. A prospective randomized double–blind clinical Ttial using a combination of olfactory ensheathing cells and Schwann cells for the treatment of chronic complete spinal cord injuries. Cell Transplant. 2014;23(Suppl 1):S35–S44.

131.

Wang

Cheng

Dai

Wang

Hua

Liu

Wang

Chen

Yue

. Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain Res. 2013;1532:76–84.

132.

Zhang

Geng

Chen

Huang

Yin

Zhang

Lou

Cao

Wang

. The potential of human umbilical cord-derived mesenchymal stem cells as a novel cellular therapy for multiple sclerosis. Cell Transplant. 2014;23(Suppl 1):S113–S122.

133.

Wang

Hua

Yang

Zheng

Niu

Cheng

Dai

Liu

Zhang

. Effect of umbilical cord mesenchymal stromal cells on motor functions of identical twins with cerebral palsy: pilot study on the correlation of efficacy and hereditary factors. Cytotherapy. 2015;17(2):224–231.

134.

Cui

Zhang

Wang

Shen

Wang

Zhang

Tong

. Transplantation of human umbilical cord-derived mesenchymal stems cells for the treatment of Becker muscular dystrophy in affected pedigree members. Int J Mol Med. 2015;35(4):1051–1057.

135.

Zhu

Poon

Liu

Leung

Wong

Feng

Tsang

Sun

Yeung

Shen

Niu

Tan

Tang

Gao

Cha

Fleischaker

Sun

Chen

Lai

. Phase I-II Clinical trial assessing safety and efficacy of umbilical cord blood mononuclear cell transplant therapy of chronic complete spinal cord injury. Cell Transplant. 2016;25(11):1925–1943.

136.

Chen

Wang

Liu

Zhang

Wang

Ren

Xiao

Wang

Huang

, Olfactory ensheathing cell neurorestorotherapy for amyotrophic lateral sclerosis patients: benefits from multiple transplantations. Cell Transplant. 2012;21(Suppl 1):S65–S77.

137.

Chen

Zhao

Bao

Xiao

Liu

Jiang

Zhou

Wang

Huang

. Intracranial transplant of olfactory ensheathing cells can protect both upper and lower motor neurons in amyotrophic lateral sclerosis. Cell Transplant. 2013;22(Suppl 1):S51–S65.

138.

Huang

Raisman

Sanberg

Sharma

, Chen L. Neurorestoratology. New York (NY): Nova Biomedical; 2015;V1:93–102.

139.

Huang

H. CNS neurorestoratology

. Beijing, China: Science Press; 2009.

140.

Siniscalco

Sych

. Stem cell transplantation for nervous system disorders in Italy, European Union, and Ukraine: Clinical approach and governmental policies. Transl Neurosci Clin. 2015;1(2):125–127.

141.

Zhou

Zhang

. Neural stem cell transplantation and postoperative management: report of 70 cases. Di Yi Jun Yi Da Xue Xue Bao. 2004;24(10):1207–1209.

142.

Guzman

Schubert

Keller-Lang

Huhn

Curt

. Human neural stem cell transplantation in chronic SCI: interim results of a phase I/II trial. Neurosurgery. 2013;60(Suppl 1):185.

143.

Shin

Kim

Yoo

Kim

Yun

Lee

Jung

Hwang

Kim

Lee

Shin

Park

. Clinical trial of human fetal brain-derived neural stem/progenitor cell transplantation in patients with traumatic cervical spinal cord injury. Neural Plast. 2015;2015:630932.

144.

Curtis

Gabel

Marsala

Ciacci

. A phase I, open-label, single-site, safety study of human spinal cord-derived neural stem cell transplantation for the treatment of chronic spinal cord injury. Neurosurgery. 2016;63(Suppl 1):168–169.

145.

Knoller

Auerbach

Fulga

Zelig

Attias

Bakimer

Marder

Yoles

Belkin

Schwartz

Hadani

. Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine. 2005;3(3):173–181.

146.

Callera

do Nascimento

. Delivery of autologous bone marrow precursor cells into the spinal cord via lumbar puncture technique in patients with spinal cord injury: a preliminary safety study. Exp Hematol. 2006;34(2):130–131.

147.

Syková

Homola

Mazanec

Lachmann

Konrádová

Kobylka

Pádr

Neuwirth

Komrska

Vávra

Stulík

Bojar

. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant. 2006;15(8–9):675–687.

148.

Chernykh

Stupak

Muradov

Sizikov

Shevela

Leplina

Tikhonova

Kulagin

Lisukov

Ostanin

Kozlov

. Application of autologous bone marrow stem cells in the therapy of spinal cord injury patients. Bull Exp Biol Med. 2007;143(4):543–547.

149.

Deda

Inci

Kürekçi

Kayihan

Ozgün

Ustünsoy

Kocabay

. Treatment of chronic spinal cord injured patients with autologous bone marrow-derived hematopoietic stem cell transplantation: 1-year follow-up. Cytotherapy. 2008;10(6):565–574.

150.

Stokic

Curt

. Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive-evoked potentials in 39 patients. Spinal Cord. 2010;48(8):649.

151.

Jones

Lammertse

Charlifue

Kirshblum

Apple

Ragnarsson

Poonian

Betz

Knoller

Heary

Choudhri

Jenkins

3rd Falci

Snyder

. A phase 2 autologous cellular therapy trial in patients with acute, complete spinal cord injury: pragmatics, recruitment, and demographics. Spinal Cord. 2010;48(11):798–807.

152.

Callera

de Melo

. Magnetic resonance tracking of magnetically labeled autologous bone marrow CD34+ cells transplanted into the spinal cord via lumbar puncture technique in patients with chronic spinal cord injury: CD34+ cells’ migration into the injured site. Stem Cells Dev. 2007;16(3):461–466.

153.

Syková

Jendelová

Urdzíková

Lesný

Hejcl

. Bone marrow stem cells and polymer hydrogels-two strategies for spinal cord injury repair. Cell Mol Neurobiol. 2006;26(7–8):1113–1129.

154.

Kishk

Gabr

Hamdy

Afifi

Abokresha

Mahmoud

Wafaie

Bilal

. Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil Neural Repair. 2010;24(8):702–708.

155.

Bhanot

Rao

Ghosh

Balaraju

Radhika

Satish Kumar

. Autologous mesenchymal stem cells in chronic spinal cord injury. Br J Neurosurg. 2011;25(4):516–522.

156.

Park

Kim

Sung

Choi

Jeon

Kim

Jeon

. Long-term results of spinal cord injury therapy using mesenchymal stem cells derived from bone marrow in humans. Neurosurgery. 2012;70(5):1238–1247.

157.

Saito

Nakatani

Iwase

Maeda

Murao

Suzuki

Fukushima

Ide

. Administration of cultured autologous bone marrow stromal cells into cerebrospinal fluid in spinal injury patients: a pilot study. Restor Neurol Neurosci. 2012;30(2):127–136.

158.

Karamouzian

Nematollahi-Mahani

Nakhaee

Eskandary

. Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clin Neurol Neurosurg. 2012;114(7):935–939.

159.

Frolov

Bryukhovetskiy

. Effects of haematopoietic autologous stem cell transplantation to the chronically injured human spinal cord evaluated by motor and somatosensory evoked potentials methods. Cell Transplant. 2012;21(Suppl 1):S49–S55.

160.

Geffner

Santacruz

Izurieta

Flor

Maldonado

Auad

Montenegro

Gonzalez

Silva

. Administration of autologous bone marrow stem cells into spinal cord injury patients via multiple routes is safe and improves their quality of life: comprehensive case studies. Cell Transplant. 2008;17(12):1277–1293.

161.

Kumar

Narayanan

Arul

Baskaran

. Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: a phase I/II clinical safety and primary efficacy data. Exp Clin Transplant. 2009;7(4):241–248.

162.

Jiang

Xiong

Wang

Yao

Kendell

Mehling

Yuan

. A clinical trial report of autologous bone marrow-derived mesenchymal stem cell transplantation in patients with spinal cord injury. Exp Ther Med. 2013;6(1):140–146.

163.

Dai

Liu

Zhang

Yang

Dai

. Transplantation of autologous bone marrow mesenchymal stem cells in the treatment of complete and chronic cervical spinal cord injury. Brain Res. 2013;1533:73–79.

164.

Mendonça

Larocca

Souza

Villarreal

Silva

Matos

Novaes

Bahia

Martinez

Kaneto

Furtado

Sampaio

Soares

Dos Santos

. Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury. Stem Cell Res Ther. 2014;5(6):126.

165.

Vaquero

Zurita

Rico

Bonilla

Aguayo

Montilla

Bustamante

Carballido

Marin

Martinez

Parajon

Fernandez

Reina

; Neurological Cell Therapy Group. An approach to personalized cell therapy in chronic complete paraplegia: the Puerta de Hierro phase I/II clinical trial. Cytotherapy. 2016;18(8):1025–1036.

166.

Kakabadze

Kipshidze

Mardaleishvili

Chutkerashvili

Chelishvili

Harders

Loladze

Shatirishvili

Kipshidze

Chakhunashvili

Chutkerashvili

. Phase 1 trial of autologous bone marrow stem cell transplantation in patients with spinal cord injury. Stem Cells Int. 2016;2016:6768274.

167.

Satti

Waheed

Ahmed

Akram

Aziz

Satti

Shahbaz

Khan

Malik

. Autologous mesenchymal stromal cell transplantation for spinal cord injury: a phase I pilot study. Cytotherapy. 2016;18(4):518–522.

168.

Chhabra

Sarda

Arora

Sharawat

Singh

Nanda

Sangodimath

Tandon

. Autologous bone marrow cell transplantation in acute spinal cord injury-an Indian pilot study. Spinal Cord. 2016;54(1):57–64.

169.

Saberi

Moshayedi

Aghayan

Arjmand

Hosseini

Emami-Razavi

Rahimi-Movaghar

Raza

Firouzi

. Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett. 2008;443(1):46–50.

170.

Saberi

Firouzi

Habibi

Moshayedi

Aghayan

Arjmand

Hosseini

Razavi

Yekaninejad

. Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases. J Neurosurg Spine. 2011;15(5):515–525.

171.

Zhou

Ning

Feng

Kong

Chen

Zheng

Ban

Liu

Wang

. Transplantation of autologous activated Schwann cells in the treatment of spinal cord injury: six cases, more than five years of follow-up. Cell Transplant. 2012;21(Suppl 1):S39–S47.

172.

Cristante

Barros-Filho

Tatsui

Mendrone

Caldas

Camargo

Alexandre

Teixeira

Oliveira

Marcon

. Stem cells in the treatment of chronic spinal cord injury: evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord. 2009;47(10):733–738.

173.

Al-Zoubi

Jafar

Jamous

Al-Twal

Al-Bakheet

Zalloum

Khalifeh

Radi

El-Khateeb

Al-Zoubi

. Transplantation of purified autologous leukapheresis-derived CD34+ and CD133+ stem cells for patients with chronic spinal cord injuries: long-term evaluation of safety and efficacy.Cell Transplant. 2014;23(Suppl 1):S25–S34.

174.

Bryukhovetskiy

. Effectiveness of repeated transplantations of hematopoietic stem cells in spinal cord injury. World J Transplant. 2015;5(3):110–128.

175.

Shin

Kim

Kang

Lee

Kim

Yoon

Choi

Kwon

. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011;20(8):1297–1308.

176.

Hur

Cho

Park

Lee

Park

Chung

. Intrathecal transplantation of autologous adipose-derived mesenchymal stem cells for treating spinal cord injury: a human trial. J Spinal Cord Med. 2016;39(6):655–664.

177.

Liu

Han

Wang

Xue

Zhu

Yan

Zheng

Guo

Wang

. Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells. Cytotherapy. 2013;15(2):185–191.

178.

Hua

Wang

Yang

Zheng

Niu

. Evaluation of somatosensory evoked potential and pain rating index in a patient with spinal cord injury accepted cell therapy. Pain Physician. 2016;19(4):E659–E666.

179.

Shroff

Gupta

. Human embryonic stem cells in the treatment of patients with spinal cord injury. Ann Neurosci. 2015;22(4):208–216.

180.

Shroff

. Human embryonic stem cell therapy in chronic spinal cord injury: a retrospective study. Clin Transl Sci. 2016;9(3):168–175.

181.

El–Kheir

Gabr

Awad

Ghannam

Barakat

Farghali

El Maadawi

Ewes

Sabaawy

. Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients. Cell Transplant. 2014;23(6):729–745.

182.

Yazdani

Hafizi

Zali

Atashi

Ashrafi

Seddighi

Soleimani

. Safety and possible outcome assessment of autologous Schwann cell and bone marrow mesenchymal stromal cell co-transplantation for treatment of patients with chronic spinal cord injury. Cytotherapy. 2013;15(7):782–791.

183.

Goni

Chhabra

Gupta

Marwaha

Dhillon

Pebam

Gopinathan

Bangalore Kantharajanna

. Safety profile, feasibility and early clinical outcome of cotransplantation of olfactory mucosa and bone marrow stem cells in chronic spinal cord injury patients. Asian Spine J. 2014;8(4):484–490.

184.

Chen

. Cell-based neurorestorative therapy for postpoliomyelitis syndrome: a case report. J Neurorestoratology. 2016;4:45–50.

185.

Chen

Xiao

Zhang

Chen

Huang

. Chromaffin cell transplantation for neuropathic pain after spinal cord injury: a report of two cases. J Neurorestoratology. 2017;5:47–50.

186.

Zhang

Meng

Liu

Huang

. Olfactory ensheathing cell transplantation for a patient with chronic sciatic nerve injury. J Neurorestoratology. 2017;5:1–4.

187.

Kalladka

Sinden

Pollock

Haig

McLean

Smith

McConnachie

Santosh

Bath

Dunn

Muir

. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet. 2016;388(10046):787–796.

188.

Steinberg

Kondziolka

Wechsler

Lunsford

Coburn

Billigen

Kim

Johnson

Bates

King

Case

McGrogan

Yankee

Schwartz

. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke. 2016;47(7):1817–1824.

189.

Chernykh

Shevela

Starostina

Morozov

Davydova

Menyaeva

Ostanin

. Safety and therapeutic potential of M2 macrophages in stroke treatment. Cell Transplant. 2016;25(8):1461–1471.

190.

Kakabadze

Kipshidze

Mardaleishvili

Chutkerashvili

Chelishvili

Harders

Loladze

Shatirishvili

Kipshidze

Chakhunashvili

Chutkerashvili

. Phase 1 trial of autologous bone marrow stem cell transplantation in patients with spinal cord injury. Stem Cells Int. 2016;2016:6768274.

191.

Vaquero

Zurita

Rico

Bonilla

Aguayo

Montilla

Bustamante

Carballido

Marin

Martinez

Parajon

Fernandez

Reina

; Neurological Cell Therapy Group. An approach to personalized cell therapy in chronic complete paraplegia: The Puerta de Hierro phase I/II clinical trial. Cytotherapy. 2016;18(8):1025–1036.

192.

Thakkar

Vanikar

Trivedi

Shah

Dave

Dixit

Tiwari

Shah

. Infusion of autologous adipose tissue derived neuronal differentiated mesenchymal stem cells and hematopoietic stem cells in post-traumatic paraplegia offers a viable therapeutic approach. Adv Biomed Res. 2016;5:51.

193.

Wang

Zhou

Zhang

Zhu

Chen

Wang

Xiao

Huang

Chi

. Autologous olfactory lamina propria transplantation for chronic spinal cord injury: three-year follow-up outcomes from a prospective double-blinded clinical trial. Cell Transplant. 2016;25(1):141–157.

194.

Nafissi

Kazemi

Tiraihi

Beladi-Moghadam

Faghihzadeh

Yadegarynia

Sadeghi

Chamani-Tabriz

Khanfakhraei

Taheri

. Intraspinal delivery of bone marrow stromal cell-derived neural stem cells in patients with amyotrophic lateral sclerosis: a safety and feasibility study. J Neurol Sci. 2016;362:174–181.

195.

Petrou

Gothelf

Argov

Gotkine

Levy

Kassis

Vaknin-Dembinsky

Ben-Hur

Offen

Abramsky

Melamed

Karussis

. Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis: results of phase 1/2 and 2a clinical trials. JAMA Neurol. 2016;73(3):337–344.

196.

Atkins

Bowman

Allan

Anstee

Arnold

Bar-Or

Bence-Bruckler

Birch

Bredeson

Chen

Fergusson

Halpenny

Hamelin

Huebsch

Hutton

Laneuville

Lapierre

Lee

Martin

McDiarmid

O’Connor

Ramsay

. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016;388(10044):576–585.

197.

Canesi

Giordano

Lazzari

Isalberti

Isaias

Benti

Rampini

Marotta

Colombo

Cereda

Dipaola

Montemurro

Viganò

Budelli

Montelatici

Lavazza

Cortelezzi

Pezzoli

. Finding a new therapeutic approach for no–option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy. J Transl Med. 2016;14(1):127.

198.

Cox

Jr Hetz

Liao

Aertker

Ewing-Cobbs

Juranek

Savitz

Jackson

Romanowska-Pawliczek

Triolo

Dash

Pedroza

Lee

Worth

Aisiku

Choi

Holcomb

Kitagawa

. Treatment of severe adult traumatic brain injury using bone marrow mononuclear cells. Stem Cells. 2017;35(4):1065–1079.

199.

Vaquero

Zurita

Bonilla

Fernández

Rubio

Mucientes

Rodriguez

Blanco

Donis

. Progressive increase in brain glucose metabolism after intrathecal administration of autologous mesenchymal stromal cells in patients with diffuse axonal injury. Cytotherapy. 2017;19(1):88–94.

200.

Bradstreet

Sych

Antonucci

Klunnik

Ivankova

Matyashchuk

Demchuk

Siniscalco

. Efficacy of fetal stem cell transplantation in autism spectrum disorders: an open-labeled pilot study. Cell Transplant. 2014;23(Suppl 1):S105–S112.

201.

Yang

Zhang

Wang

Liu

Zheng

Yang

Luan

. Combined transplantation of neural precursor cells and olfactory ensheathing cells for the treatment of X-linked adrenoleukodystrophy in children. J Neurorestoratology. 2017;5:93–101.

202.

Huang

Mao

Feng

, Chen L. 2016 yearbook of neurorestoratology. J Neurorestoratology. 2017;5:111–115.