Sage Journals: Discover world-class research

Abstract

Spinal cord injury (SCI) is a devastating disease, with a high rate of disability. In this meta-analysis, we aimed to comprehensively assess the efficacy and safety of mesenchymal stem cells (MSCs) in treating clinical SCI patients. We systematically searched the PUBMED, EMBASE, Chinese Biomedical (CBM), Web of Science and Cochrane databases using the strategy of combination of free-text words and MeSH terms. The indicators of the American Spinal Injury Association (ASIA) impairment scale (AIS)-grading improvement rate and adverse effects were displayed with an overall relative risk (RR). For the continuous variables of the ASIA motor score, light-touch score, pinprick score, activities of daily living (ADL) score, and residual urine volume, we used odds ratio (OR) to analyze the data. Eleven studies comprising 499 patients meeting all inclusion and exclusion criteria were included. No serious heterogeneity or publication bias was observed across each study. The results showed that significant improvements of total AIS grade (RR: 3.70; P < 0.001), AIS grade A (RR: 3.57; P < 0.001), ASIA sensory score (OR: 8.63; P < 0.001) and reduction of residual urine volume (OR: −36.37; P = 0.03) were observed in experimental group compared with control group. However, no significant differences of motor score (OR: 1.37, P = 0.19) and ADL score (OR: 2.61, P = 0.27) were observed between experimental and control groups. In addition, there were no serious and permanent adverse effects after cell transplantation. Cell transplantation with MSCs is effective and safe in improving the sensory and bladder functions of SCI patients.

Keywords

spinal cord injury mesenchymal stem cell cell transplantation meta-analysis

Introduction

Spinal cord injury (SCI) is a devastating disease, with a high rate of disability. Patients with SCI always suffer from paralysis, locomotor and sensory dysfunction, urinary incontinence or gastrointestinal dysfunction^1,2. The incidence of SCI is 27–83 per million in the US and 10–30 per million in Europe^3,4, which poses a great burden on society. Therefore, there is an urgency to develop an effective therapy for cure of these patients.

The underlying mechanisms of SCI include direct mechanical damages and secondary injuries. Direct mechanical damages involve compression and contusion from the fractured and dislocated bone fragments and discs around the spinal cord⁵. Secondary injuries include neural apoptosis, spinal cord swelling, inflammatory response, oxidative stress and electrolyte disturbance^6
–8. Both primary and secondary injuries can cause devastating tissue damage, axonotmesis, demyelination, Wallerian degeneration, syringomyelia, and glial scar formation^9
–11. Many methods have been explored to treat SCI, including surgery, drugs, and rehabilitation, however, no treatment with good efficacy has been reported.

Recently, stem cell transplantation has attracted attention and is reported to be an effective treatment in treating SCI in animal models^12,13. A variety of stem cell types have shown their potential for transplantation, such as neural stem cells¹⁴, mesenchymal stem cells (MSCs)⁴ , Schwann cells¹⁵, embryonic stem cells¹⁶, and induced pluripotent stem cells^17,18. Among these, MSCs have played a pivotal role in repairing the damaged spinal cord. MSCs can not only differentiate and replace the damaged cells, but also secrete neuroprotective cytokines, including vascular endothelial growth factor (VEGF), glial-cell-line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), which all increase neural regeneration, strengthen axon growth, and revive damaged neurons^19,20. Currently, the efficacy and safety of cell transplantation with MSCs have been verified in the animal SCI models. However, it is unclear whether MSCs have the same efficacy in treating SCI in humans as in animals. No meta-analysis has extensively evaluated the efficacy and safety of MSCs in treating patients with SCI.

Therefore, we conducted this meta-analysis to comprehensively assess the efficacy and safety of MSCs in treating clinical patients by evaluating outcomes including the American Spinal Injury Association (ASIA) motor score, ASIA sensory score (including light-touch and pinprick scores), ASIA Impairment Scale (AIS)-grading improvement rate, activities of daily living (ADL) score, residual urine volume, and adverse events.

Materials and Methods

Protocol

We conducted this meta-analysis based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA)²¹ (Supplemental Table 1).

Search Strategy

The databases of PUBMED, EMBASE, Chinese Biomedical (CBM), Web of Science and Cochrane were systematically searched for eligible studies (up to 25 July 2018). The search strategy consisted of free-words and MeSH terms as follows: (a) “mesenchymal stromal cells” or “MSCs,” and (b) “spinal cord injury” or “SCI,” (c) patient. In addition, other potential eligible studies were identified manually from references of included studies or other reviews pertaining to this topic.

This selection process of eligible articles was conducted by two authors independently (P Xu and X Yang).

Selection Criteria

The inclusion criteria are listed as: (a) Randomized controlled trials or other comparative studies; (b) patients diagnosed with SCI based on ASIA international standards for neurological classification; (c) patients only receiving transplantation of MSCs, or MSCs combined with rehabilitation; (d) the data regarding one or more of the following outcomes could be extracted: AIS grading, ASIA sensory score (including light-touch score and pinprick score), locomotor function, residual urine volume, ADL score or adverse effects; and (e) no overlapping data among different studies.

The exclusion criteria are listed as: (a) The study did not meet the inclusion criteria; (b) reviews, editorials, clinical conference, abstracts, case reports, comments, congresses; (c) non-human studies; (d) single-arm studies.

Data Extraction and Quality Assessment

We extracted the following data from included studies. (a) Identity: authors, years. (b) Patients included in each study: age, duration of injury, size of each group. (c) Treatments: treatment strategy, transplantation methods, cell sources, cell number, follow-up period. (d) Outcomes: AIS grading, ASIA motor score, ASIA sensory score (including light-touch and pinprick scores), ADL, residual urine volume, incidence of adverse effects.

The data of interest from included articles were extracted and processed by two authors, independently (Xu PF and Yang XL). Any disagreement was settled by discussion.

The risks of bias within the included studies were evaluated with the domain-based Cochrane Collaboration tool²². Detailed content of this assessment tool included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Any dispute was resolved by discussion.

Types of Outcome Measures

The following indicators were applied to assess the efficacy and safety of treatment with MSCs for SCI patients: AIS grading improvement rate, ASIA motor score, ASIA sensory score (including light-touch and pinprick scores), ADL score, residual urine volume, and adverse effects.

Statistical Analysis

This meta-analysis was completed with Stata 14 and Review Manager version 5.0 software (Cochrane Collaboration, software update, Oxford, UK), which was provided by the Cochrane Collaboration. The indicators of AIS grading improvement rate and adverse effects were displayed with an overall relative risk (RR), with corresponding 95% confidential interval (CI). For the continuous variables of ASIA motor score, light-touch score, pinprick score, ADL score, and residual urine volume, we used odds ratio (OR), with corresponding 95% CI to analyze the data.

We used the chi-squared value test and inconsistency index (I²) to assess the heterogeneity across each study. A value of P < 0.1 or I² > 50% was deemed to have significant heterogeneity, a random-effect model was then used to analyze the data. Otherwise, the fixed-effect model was used. Subgroup analysis was used to find potential source of heterogeneity^23,24. We adopted the Egger funnel plot and Egger’s test to test publication bias with Stata14.0 (StataCorp LP, College Station, TX, US)^25,26, with P < 0.05 indicating significant asymmetry²⁷.

Results

Study Screen

Searches of the PUBMED, EMBASE, Chinese Biomedical (CBM), Web of Science and Cochrane databases identified 566, 153, 369, 215 and 19 studies, respectively. After removing duplicated studies, 987 studies remained for screening by title and abstract. Subsequently, 59 records with full text were assessed. Finally, 11 studies^{28

–37} containing a total number of 499 cases were included in this meta-analysis (Fig 1).

Fig 1.

Flow Diagram of the Study Selection Process.

Study Characteristics

The basic characteristics of all 11 studies are summarized in Table 1. The sample sizes ranged from 20 to 96. Nine studies were conducted in China^{28,29,31

–38}, one study was conducted in Iran³⁰, and another was performed in Egypt³¹. Four studies were reported in English^28

–31, and the other seven were in Chinese^32

–38. All studies chose rehabilitation therapy as the control. The MSCs originated from umbilical cord in five studies^{29,32,34,37,38} and bone marrow in six studies^{28,30,31,33,35,36}. Six studies adopted subarachnoid injection as the process used for cell transplantation^{28

–33,38}; two studies^35,37 used intravenous injection and the other two studies reported both methods^34,36. The course of SCI ranged from 1 week to 9 years and the follow-up period ranged from 3 to 23.4 months. For reporting the outcomes, five studies reported AIS grading improvement rate^{28,30,31,34,36}, ten studies reported ASIA motor score^{28,29,31

–38}, five studies reported ASIA light-touch and pinprick scores^{28,31,33,34,38}, seven studies reported ADL score^28,29,32 ^- ^34,36,37, three studies reported residual urine volume^28,29,36, and 11 studies reported some mild adverse effects^{28

–38}.

Table 1.

Characteristics of Included Studies.

Author(s)	Year	Size	Treatment/control	M/F	Age (years)	Treatments	Cell source	Method of transplantation	Cell number	Duration	Assessment	Follow up	Adverse events
Xie et al.	2007	24	11	9/2	18-49	R + SCT	BMMSCs	Intravenous/subarachnoid	(4.08–10.20) × 10⁷	1–10 months	ASIA sensation score; ASIA motor score; ADL (BI); residual urine volume; AIS grading	3 months	Fever (7); headache (2); abdominal distention (1); numbness (1)
Xie et al.	2007	24	13	10/3	21–53	R						3 months	None
Guo et al.	2012	24	12	11/1	29	R + SCT	UCMSCs	Subarachnoid	(2–5) × 10⁷	2.3 months	ASIA sensation score; ASIA motor score; ADL	5 months	None
Guo et al.	2012	24	12	10/2	31	R				2.5 months	ASIA sensation score; ASIA motor score; ADL	5 months	None
Li	2012	30	15	12/3	37.36	R + SCT	UCMSCs	Intravenous/subarachnoid	5 × 10⁷	1 months–9 years	AIS grading; ASIA motor score; ASIA light-touch score; ASIA pinprick score; ADL; SEP; MCS; SCV; EMG	4 months	Fever (2); headache (4); backache (3)
Li	2012	30	15	10/5	37.67	R				1 months–9 years		4 months	None
Dai et al.	2013	40	20	14/6	34.7	R + SCT	BMMSCs	Subarachnoid	2 × 10⁷	51.9 months	AIS grading; ASIA motor score; ASIA light-touch score; ASIA pinprick score; residual urine volume; EMG; PSSEP; MRI	6 months	Fever (2); headache (1); pain and numbness (2)
Dai et al.	2013	40	20	14/6	35.1	R				43.2 months		6 months	None
Guo et al.	2014	80	40	30/10	37.25	R + SCT	BMMSCs	Unknown	1.5 × 10⁴	None	AIS grading; ASIA motor score; ASIA light-touch score; ASIA pinprick score; ADL	None	Fever (1)
Guo et al.	2014	80	40	33/7	36.37	R				None		None	None
Cheng et al.	2014	20	10	Uknown	32.25	R + SCT	UCMSCs	Subarachnoid	4 × 10⁷	21.4 months	ASIA sensation score; ASIA motor score; muscle tension scale; ADL; urodynamic examination	6 months	Radiating neuralgia (1)
Cheng et al.	2014	20	10	Uknown	32.25	R				18.57 months		6 months	None
Zhang et al.	2015	30	15	11/4	35.5	R + SCT	UCMSCs	Subarachnoid	4 × 10⁷	21.3 ± 5.7 months	AIS grading; ASIA motor score; ASIA light-touch score; ASIA pinprick score	6 months	Fever (7); headache (2); numbness (4)
Zhang et al.	2015	30	15	11/4	35.7	R				21.3 ± 5.7 months		6 months	None
Zhang et al.	2012	60	30	50/10	18–45	R + SCT	UCMSCs	Intravenous	1 × 10⁷	1–10 months	ASIA sensation score; ASIA motor score	3 months	Fever (1); headache (2)
Zhang et al.	2012	60	30	50/10	18–45	R				1–10 months	ASIA sensation score; ASIA motor score	3 months	None
Kishk et al.	2010	64	44	36/8	31.7	R + SCT	BMMSCs	Subarachnoid	3.75 × 10⁸ to 7.5 × 10⁸	3.6 years	Barthel trunk muscle assessment; MCS; FAC; ASI grading; ASIA sensation score; ASIA motor score; SSEP	6 months	Neuropathic pain (24); post-infectious myelitis (1)
Kishk et al.	2010	64	20	15/5	33.8	R				3.7 years		6 months	None
Karamouzian et al.	2012	31	11	7/4	33.2	R + SCT	BMMSCs	Subarachnoid	7 × 10⁵ to 1.2 × 10⁶	23.7 ± 8.4 days	AIS grading; ASIA motor score	20.3 months	None
Karamouzian et al.	2012	31	20	17/3	33.5	R				23.7 ± 8.4 days	AIS grading; ASIA motor score	23.4 months	None
Xiao et al.	2012	96	38	25/13	42.3	R + SCT	BMMSCs	Subarachnoid	1.4 × 10⁷	1 week	ASIA sensation score; ASIA motor score	6 months	Fever (5)
			32	21/11	41.5	R + SCT	BMMSCs	Intravenous	1.4 × 10⁷				Fever (5)
			26	17/9	41.2	R							None

M: male; F: female; R: rehabilitation; SCT: stem cell transplantation; BMMSCs: bone marrow mesenchymal stem cells; UCMSCs: umbilical cord mesenchymal stem cells; ASIA: American Spinal Injury Association; AIS: ASIA impairment scale; ADL: activities of daily living; MCS: motor nerve conduction studies; SEP: sensory-evoked potential; SCV: sensory nerve conduction studies; EMG: electromyography; FAC: functional ambulation categories ; SSEP: somatosensory evoked potential; BI: barthel index; PSSEP: paraspinal somatosensory evoked potential.

Methodological Quality of Included Studies

We used the standard Cochrane Collaboration tool to evaluate the risks of bias within included studies, and the results of methodological quality of each study are shown in Fig 2. Ten studies reported random sequence generation and one study did not mention it. Additionally, three studies had the details of blinding of outcome assessment, one study lacked blinding of outcome assessment and the others did not state the blinding of outcome assessment. Overall, the methodological quality of included studies was acceptable.

Fig 2.

Risk of Bias Percentile Chart. (2A) Risk of bias graph: A plot of the distribution of review authors’ judgements across studies for each risk of bias item; (2B) Risk of bias summary: A summary table of review authors’ judgements for each risk of bias item for each study.

Efficacy of Treatment

American Spinal Injury Association Impairment Scale Grading Improvement Rate

Five studies containing 189 cases reported AIS grading improvement rate, low heterogeneity was observed across each trial (P = 0.25, I² = 26%, Fig 3A). A fixed-effects model was applied to evaluate the AIS improvement rate. The results indicated significant improvements of total AIS grade and AIS grade A in the experiment group compared with control group (total AIS grade: RR: 3.70; 95% CI 2.63–6.25; P < 0.001; AIS grade A: RR: 3.57; 95% CI 2.5–6.67; P < 0.001, respectively; Fig 3A and 3B), however, no significant difference was found in AIS grading B/C/D (RR: 4.46; 95% CI 0.42–47.34; P = 0.22; Fig 3C).

Fig 3.

Forest Plot of Comparison: Cell Transplantation Group Versus Control Group.

American Spinal Injury Association Sensory Score

Ten studies containing 468 cases reported ASIA sensory score (including ASIA light-touch and pinprick scores); low heterogeneity was observed among included studies (P = 0.16, I² = 31%). A fixed-effects model was applied to evaluate the ASIA sensory score. The results indicated significant improvements of general ASIA sensory score, ASIA light-touch score and ASIA pinprick score in the experiment group, compared with the control group (general ASIA sensory score: OR: 8.63; 95% CI 4.84–12.41, P < 0.001; ASIA light-touch score: OR: 4.57; 95% CI 0.74–8.4, P = 0.02; ASIA pinprick score: OR: 4.92; 95% CI 1.59–8.25, P = 0.004; Fig 3D, 3E and 3F).

American Spinal Injury Association Motor Score

Ten studies containing 468 cases reported ASIA motor score; low heterogeneity was observed across each trial (P = 0.43, I² = 1%). A fixed-effects model was applied to evaluate the ASIA motor score. The results showed that no significant improvements of ASIA motor score were observed in the experiment group compared with the control group (OR: 1.37; 95% CI 0.70–3.44; P = 0.19; Fig 3G).

Activities-of-Daily-Living Score

Seven studies containing 278 cases reported ADL score; moderate heterogeneity was observed (P = 0.02, I² = 59%). Therefore, the random-effects model was applied to evaluate the ADL score. The results showed that no significant improvements of ADL score were observed in the experiment group compared with the control group (OR: 2.61; 95% CI 2.04–7.26; P = 0.27; Fig 3H).

Residual Urine Volume

Three studies containing 84 cases reported residual urine volume; moderate heterogeneity was observed among included trials (P = 0.02, I² = 73%). A random-effects model was applied to evaluate the residual urine volume. The results showed that significant reduction of residual urine volume was observed in the experiment group compared with the control group (OR: 36.37; 95% CI 68.45–4.29; P = 0.03; Fig 3I).

Safety

Eleven studies containing 499 cases reported adverse effects; low heterogeneity was observed across each trial (P = 0.11, I² = 38%). The fixed-effects model was then employed in the RR pooled analyses. The results showed that patients receiving cell transplantation of MSCs experience more toxicity than that of the control group (RR: 20.34; 95% CI 8.09–51.18, P < 0.001; Fig 3J). Common adverse effects include fever, headache, backache, numbness, and abdominal distension, which were alleviated spontaneously or following treatment intervention. However, no serious or permanent adverse effects, such as death, tumor, or immune reaction, were observed during follow up.

Subgroup Analysis

We performed subgroup analysis based on cell sources and follow-up period. For analyzing the effects of cell transplantation on motor function and self-care ability, no significant differences were observed between experiment and control groups with different cell sources and follow-up periods (P > 0.05; Fig 4A–4G). However, regarding the adverse effects of cell transplantation, the experiment group showed a higher rate of adverse effects than that in the control group, no matter which different cell sources or follow-up periods (P < 0.05; Fig 4H–4K).

Fig 4.

Forest Plot of Subgroup Analysis Based on Cell Source and Follow-Up Periods.

Publication Bias

The Egger’s funnel plot and rank correlation test showed no significant publication bias across each study regarding sensory score, motor function, and adverse effects (P = 0.387, P = 0.091 and P = 0.07, respectively; Fig 5A–5C). For other indicators, the assessment of publication bias cannot be conducted due to insufficient number of studies (n < 10).

Fig 5.

Funnel Plot of Publication Bias.

Discussion

This meta-analysis included 11 studies and comprehensively evaluated the safety and efficacy of MSC transplantation for treating patients with SCI. Although the efficacy of this method for treating SCI patients remains unclear, this study showed that when compared with rehabilitation therapy, MSC transplantation significantly improved the neurological functions, including ASIA light touch, pinprick, ADL, and bladder function. However, this meta-analysis found that no significant difference was observed for the improvement of motor score, and the patients who received MSC transplantation displayed some mild and temporary side effects.

MSCs could be extracted from autologous bone marrow, umbilical cord or adipose tissue^39,40. In the animal studies, MSCs have displayed many advantages in the treatment of SCI. Some studies showed that MSCs could survive in the site of injury and differentiate into different types of cells (neurons, oligodendrocytes, vascular endothelial and astrocytes)⁴¹. In addition, MSCs can also secrete neuroprotective cytokines, including VEGF, GDNF, and BDNF, which support neural regeneration, promote axon growth, and activate damaged neurons^19,20. Furthermore, MSCs are reported to inhibit glial scar formation, alleviate scar obstructions, and activate endogenous neural stem cells^42,43.

Although some studies demonstrated no advantages with stem cell transplantation in the treatment of SCI³⁰, most of the studies included in this meta-analysis indicated that MSC transplantations could significantly improve the sensory functions, including light touch and pinprick. Their results showed that sensory functions were improved in two respects. On the one hand, the improvement was reflected on the downward level of damaged spinal cord with loss of sensation. On the other hand, the sensory functions were improved from insensitivity or weak sensation to strong sensation. In addition, regarding AIS grading, cell transplantation could significantly improve AIS grading in all patients and in patients with AIS grade A before cell transplantation. However, for the patients with AIS grade B or lower before cell transplantation, no advantage was gained from cell transplantation. Furthermore, some studies reported that cell transplantation could significantly improve motor functions^32,33, but the results of the present study demonstrated that no significant difference was observed between patients receiving cell transplantation and those in the rehabilitation group. Seven studies reported self-care ability. The results of this study showed that no significant improvement of self-care ability was observed in both short-term and long-term follow up after cell transplantation. Regarding bladder function, urine residual volume was significantly reduced after cell transplantation. Cheng et al. also performed urodynamic examination. Their results showed that maximum bladder capacity increases, residual urine volume decreases, maximum detrusor pressure decreases, and maximum urinary flow rate increases²⁹.

Although the results showed some adverse effects in the present study, all were only displayed as temporary and light side effects, including fever, headache, backache, numbness, and abdominal distension, primarily caused by spinal puncture. No devastating and long-term adverse effects, such as wound infection, cerebrospinal fluid leakage from incision, or intracranial infection were observed in patients receiving stem cell transplantation, indicating the safety of cell transplantation.

Limitations

Some limitations cannot be ignored in this study. First, only 11 studies were included in this study. Some important subgroup analyses, such as different courses of disease and number of cells given to the patients, could not be performed. Second, we only included the papers published in English and Chinese in this meta-analysis, which may leave out other eligible studies that were reported in other languages. In addition, most of these studies included were conducted in China. There may be some differences of the effects and safety in other populations. Therefore, the results should be interpreted cautiously due to the limited data, although the results of this meta-analysis are robust. Third, no significant publication bias in the overall analysis was observed in this study, but many factors, including stem cell preparation and identification, social economic level, or nursing care could have impacts on the outcomes of stem cell transplantation for SCI. Therefore, multi-centric and large-sample randomized controlled studies with reasonable random sequence generation, adequate allocation concealment, and low risk of reporting bias are required to provide more medical evidence base.

Conclusions

Cell transplantation with MSCs is effective and safe in improving the sensory and bladder functions in SCI patients; however, its effect on motor function is unclear.

Supplemental Material

Supplemental_materials - The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal Cord Injury Patients: A Meta-Analysis and Systematic Review

Supplemental_materials for The Efficacy and Safety of Mesenchymal Stem Cell Transplantation for Spinal Cord Injury Patients: A Meta-Analysis and Systematic Review by Panfeng Xu, and Xianliang Yang in Cell Transplantation

Footnotes

Ethical Approval

Ethical Approval is not applicable to this study.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

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

Supplemental Material

Supplemental material for this article is available online.

References

Kooijmans

Post

MWM

Stam

Van der Woude

LHV

Spijkerman

DCM

Snoek

Bongers-Janssen

HMH

Van Koppenhagen

Twisk

Bussmann

JBJ

; ALLRISC Group. Effectiveness of a self-management intervention to promote an active lifestyle in persons with long-term spinal cord injury: The HABITS randomized clinical trial. Neurorehabil Neural Repair. 2017;31(12):991–1004.

Ying

Daqing

Raisman

. Functional repair of rat corticospinal tract lesions does not require permanent survival of an immuno-incompatible transplant. Cell Transplant. 2016;25(2):293–299.

Wyndaele

. Incidence, prevalence and epidemiology of spinal cord injury: What learns a worldwide literature survey? Spinal Cord. 2006;44(9):523–529.

Matyas

Stewart

Goldsmith

Nan

Skeel

Rossignol

Dunbar

. Effects of bone-marrow-derived MSC transplantation on functional recovery in a rat model of spinal cord injury: Comparisons of transplant locations and cell concentrations. Cell Transplant. 2017;26(8):1472–1482.

Rowland

Hawryluk

Kwon

Fehlings

. Current status of acute spinal cord injury pathophysiology and emerging therapies: Promise on the horizon. Neurosurg Focus. 2008;25(5):E2.

Taoka

Okajima

. Spinal cord injury in the rat. Prog Neurobiol. 1998;56(3):341–358.

Cheng

Bosco

Sun

Chen

Tai

Didier

Fan

Ren

. Neural stem cell-conditioned medium suppresses inflammation and promotes spinal cord injury recovery. Cell Transplant. 2017;26(3):469–482.

Zhou

Ouyang

Lin

Chen

Liu

Zhou

Wang

. Protective role of β-carotene against oxidative stress and neuroinflammation in a rat model of spinal cord injury. Int Immunopharmacol. 2018;61:92–99.

Wang

Liu

Zhang

Chu

Wang

Liu

Wang

Liu

Wang

. Effect of glial cells on remyelination after spinal cord injury. Neural Regen Res. 2017;12(10):1724–1732.

10.

Kakulas

Kaelan

. The neuropathological foundations for the restorative neurology of spinal cord injury. Clin Neurol Neurosurg. 2015;129(suppl 1):S1–S7.

11.

Baek

Cho

Kim

. Elucidation of gene expression patterns in the brain after spinal cord injury. Cell Transplant. 2017;26(7):1286–1300.

12.

Wyatt

Keirstead

. Stem cell-based treatments for spinal cord injury. Prog Brain Res. 2012;201:233–252.

13.

Cho

Kim

Kang

Yim

Park

Min

Lee

Shin

Lim

. Functional recovery after the transplantation of neurally differentiated mesenchymal stem cells derived from bone marrow in a rat model of spinal cord injury. Cell Transplant. 2016;25(7):1423.

14.

Fan

Liu

Wang

Xue

Zhao

. Transplantation of hypoxic preconditioned neural stem cells benefits functional recovery via enhancing neurotrophic secretion after spinal cord injury in rats. J Cell Biochem. 2018;119(6):4339–4351.

15.

Bunge

Monje

Khan

Wood

. From transplanting Schwann cells in experimental rat spinal cord injury to their transplantation into human injured spinal cord in clinical trials. Prog Brain Res. 2017;231:107–133.

16.

Romanyuk

Amemori

Turnovcova

Prochazka

Onteniente

Sykova

Jendelova

. Beneficial effect of human induced pluripotent stem cell-derived neural precursors in spinal cord injury repair. Cell Transplant. 2015;24(9):1781–1797.

17.

Nagoshi

Okano

. IPSC-derived neural precursor cells: potential for cell transplantation therapy in spinal cord injury. Cell Mol Life Sci. 2018;75(6):989–1000.

18.

Iyer

Wilems

Sakiyama-Elbert

. Stem cells for spinal cord injury: Strategies to inform differentiation and transplantation. Biotechnol Bioeng. 2017;114:245–259.

19.

Lee

Yun

Che

Lee

. Hypoxia-specific, VEGF-expressing neural stem cell therapy for safe and effective treatment of neuropathic pain. J Control Release. 2016;226:21–34.

20.

Itakura

Kobayashi

Nishimura

Iwai

Takano

Iwanami

Toyama

Okano

Nakamura

. Control of the survival and growth of human glioblastoma grafted into the spinal cord of mice by taking advantage of immunorejection. Cell Transplant. 2015;24(7):1299–1311.

21.

Liberati

Altman

Tetzlaff

Mulrow

Gøtzsche

Ioannidis

JPA

Clarke

Devereaux

Kleijnen

Moher

. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. PLOS Med. 2009;6:e1000100.

22.

Anonymous. Research and Markets: Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev; 2008.

23.

Higgins

Thompson

Deeks

Altman

. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560.

24.

Leeflang

Deeks

Gatsonis

Bossuyt

. Systematic reviews of diagnostic test accuracy. Ann Intern Med. 2008;149(12):889–897.

25.

Deeks

Macaskill

Irwig

. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol. 2005;58(9):882–893.

26.

Egger

Davey

Schneider

. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634.

27.

Zhao

Zhang

Wang

. A meta-analysis on the diagnostic performance of 18F-FDG and 11C-methionine PET for differentiating brain tumors. AJNR Am J Neuroradiol. 2014;35(6):1058–1065.

28.

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.

29.

Cheng

Liu

Hua

Dai

Wang

Gao

. Clinical observation of umbilical cord mesenchymal stem cell transplantation in treatment for sequelae of thoracolumbar spinal cord injury. J Transl Med. 2014;12:253.

30.

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.

31.

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.

32.

Guo GH Shen

. Clinical studies of umbilical cord blood mesenchymal stem cells transplantation on spinal cord injury. Chinese J Pract Med. 2012;39(10):58–60.

33.

Guo

Qin

Dai

Shao

Cheng

Zhang

Liu

. Bone marrow mesenchymal stem cells in the treatment of spinal cord injury. Chin J Exp Surg. 2014;31(11):2605–2607.

34.

. The Clinical Study of Stem Cells Transplantation for Treatment of Spinal Cord Injury. Kuming: Kuming Medical University. 2012.

35.

Xiao

Zhu

Guo

Geng

Zhang

Zhong

Han

. Efficacy observation of autologous bone marrow-derived mesenchymal stem cell therapy on early spinal cord injury. Zhonghua Shengwu Yixue Gongcheng Zazhi. 2014;20:7–11.

36.

Xie

Cui

Zhu

Song

Shi

Hou

Shen

. Curative effect of autologous mesenchymal stem cell transplantation on spinal cord injury. J Clin Rehabil Tissue Eng Res. 2007;11:1277–1279.

37.

Zhang

Gao

Yang

. Clinical efficacy of mesenchymal stem cell transplantation. Asia Pacific Tradition Med. 2012;8(3):116–117.

38.

Zhang

Dai

Liu

Wang

. Umbilical cord mesenchymal stem cell transplantation for spinal cord injury. Zhonghua Shiyong Zhenduan yu Zhiliao Zazhi. 2015;29:478–480.

39.

Jayaram

Ikepeama

Rothenberg

Malanga

. Bone marrow derived and adipose derived mesenchymal stem cell therapy in primary knee osteoarthritis: A narrative review. PM R. Epub ahead of print 7 August 2018. DOI: 10.1016/j.pmrj.2018.06.019.

40.

Mahmoudian-Sani

Mehri-Ghahfarrokhi

Hashemzadeh-Chaleshtori

Saidijam

Jami

. Comparison of three types of mesenchymal stem cells (bone marrow, adipose tissue, and umbilical cord-derived) as potential sources for inner ear regeneration. Int Tinnitus J. 2017;21(2):122–127.

41.

Wang

Yuan

Xie

. Mesenchymal stem cell-based immunomodulation: Properties and clinical application. Stem Cells Int. 2018;2018:1–12.

42.

Cao

Feng

. Human umbilical cord mesenchymal stem cells and the treatment of spinal cord injury. Chin Med J (Engl). 2009;122(2):225–231.

43.

Luo

Xia

Zhang

Meng

Cui

Chen

Lin

Zhu

Feng

. Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells. Crit Care Med. 2010;38(11):2181–2189.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.33 MB