Abstract
The 7th Pan Pacific Symposium on Stem Cells and Cancer Research was held in Taichung, Taiwan, on April 12–14, 2014. The main themes for this symposium were advancing translational and regenerative medicine in stem cell therapy, current clinical applications of induced pluripotent stem cells (iPSC), nanotechnology and medical devices, new drug discovery and development, and patent validation and patent appraisals. Among them, 19 topics were selected for this special issue.
Identification and Preparation of Human Stem Cells: Enhancing Production and Function
Stem cells used for clinical therapy are considered to be new drugs when applied toward diseases. Therefore, stem cell identification and preparation need to be standardized. Various methods and technologies may be adopted to modify the procedures for enhancing stem cell productivity and function. Chou et al. review the role of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, in stem cell maintenance and lineage specification, such as neurogenesis, osteogenesis, or hepatogenesis, etc. The maintenance of multipotency of various stem cells (hematopoietic stem cells, neural stem cells) depends on the existence of EZH2. The fate of neural stem cell differentiation into neurons, astrocytes, and oligodendrocytes also relies on EZH2. Overexpression of EZH2 forces neural stem cells to turn into oligodendrocytes; on the other hand, downregulation of EZH2 turns neural stem cells into the neuronal and astrocytic lineage. In order to maintain the stemness of embryonic stem cells (ESCs), Lo et al. found that leukemia inhibitory factor and fibroblast growth factor (FGF2) are sufficient for isolation and expansion of ESCs via the molecular mechanisms of phosphorylation of signal transducer and activator of transcription 3, AKT, and extracellular signal-regulated kinase 1/2 signaling system.
Currently, the resources of stem cells applied for clinical trials are mainly from bone marrow, cord blood, and adipose tissue. Here, Ding et al. describe an important source of stem cells from human umbilical cord, in which mesenchymal stem cells can be identified, cultured, and expanded. Cell characteristics and clinical applications, including banking and safety, are reviewed. Not only applied in regenerative medicine, the molecular mechanisms of anticancer effects in breast cancer, lung cancer, and lymphoma are described.
Another possible source of stem cells in diseases, such as bone marrow failure patients, is the extramedullary hematopoietic system (EMH). Chiu et al. extensively review the EMH, including spleen, liver, lymph nodes, and adipose tissue. Animal models of EMH induced by drugs [cydophosphamide/granulocyte colony stimulating factor (G-CSF)], cytokines [interleukin (IL)-27 and IL-3], and growth factors (FGF2) are described.
Combination Therapy in CNS Regeneration Medicine
Central nervous system (CNS) diseases involve different molecular mechanisms of pathophysiology. The same is true for the restoration of CNS function by the combination therapy of neural stimulation and drugs. Sun et al. studied the role of microRNAs (miRNAs) in a gerbil stroke model. They found that Sarcophilus harrisii miR-24 (shamiR-24), Ornithorhynchus anatinus let-7b-3p (oan-let-7b-3p) and related transactivation response DNA-binding protein (TDP43), Mus musculus miR-125b-5p (mmu-miR-125b-5p) and mmu-miR-132–5p, related fused in sarcoma/translocated in liposarcoma, and mmu-miR-378a-5p and related heat shock protein 70 (HSP70) are involved in the cerebral ischemic tolerance and neuroregeneration.
Endogenous stem cell therapy by using G-CSF is currently being studied in different diseases. The movement of these stem cells in the brain is an important issue. Yuan et al. investigate the niche and the movement of neural stem cells in normal rats. They found that the rostral migratory stream vasculature, enriched in vascular endothelial growth factor, forms a leaky blood–brain barrier together with adjacent astrocyte. This area serves not only the niche and reserve for neural stem cells but also the migratory pathway for these endogenous stem cells. This rostral migratory stream vasculature is also an important route for stem cells delivered intranasally entering the injured brain. Wei et al. found that the intranasal delivery of bone marrow mesenchymal stem cells in neonatal stroke animals reduces infarct size, promotes neurovascular repair, and improves neural function and social behavior recovering.
Neural inflammation of injured neural tissue caused by the activated microglia/macrophages is another mechanism causing neural degeneration. Li et al. reported that Lycium barbarum (wolfberry) polysaccharide (LBP) has a neuroprotective effect on optic nerve injury via an inhibition mechanism in the activation of microglia/macrophages. In addition, Bie et al. showed that LBP alters autophagy in the electrical stimulation-induced injury of microglia. The latter is a potential side effect of the use of visual prostheses for the improvement of blindness or visual impairment.
Electric stimulation for promoting nerve regeneration has been adapted as a physical therapy for a long time. Young extensively reviews its role in motor recovery in spinal cord injury. He concludes that functional electrical stimulation facilitates synaptic formation and motor recovery after spinal injury.
Regarding traumatic brain injury, de la Peña et al. found that the combination of human umbilical cord blood cell therapy and G-CSF treatment has a better neuroprotective effect and facilitates reconstruction of synaptic circuitry.
Another kind of stem cells identified from human placenta-derived multipotent stem cells (hPDMCs) was applied in studying ischemic brain injury rats by Wu et al. They demonstrate that therapy with hPDMCs in acute stroke animals attenuates microglia inflammation, reduces cortical infarction, and improves behavior recovery. Fan et al. review the current status of the definition and ongoing therapy of cerebral palsy, including several clinical trials of stem cell therapy being conducting worldwide. Among these trials including umbilical cord blood cells, either allogeneic or autologous are the most often used stem cells, and some of them are combined with erythropoietin.
Cell Good Manufacturing Practice (CGMP) Strategies of Clinical Application of Adipose-Derived Stem Cells (ADSCs)
Yeh et al. review the cGMP strategies of ADSC processing and current clinical trials in treating neurological diseases. Cell characteristics, distribution, and toxicology of ADSCs need to be clarified and standardized. Clinical trials in chronic stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, traumatic brain injury, and peripheral nerve injury using ADSCs are described. The preconditioning of ADSCs is also an important technology in developing cell therapy. Rajamani et al. studied the effect of trans-cinnamaldehyde (TC) on preconditioning ADSCs. They found that TC preconditioning enhances sirtuin 1 expression and increases telomerase activity at the cellular level. These preconditioned ADSCs have a better liver regenerative effect after being transplanted into damaged liver than nonpreconditioned ADSCs. Another possible clinical application of ADSCs is used to treat injured tendons. Chen et al. studied the therapeutic effect of ADSCs in rotator cuff injury in rats. They found that direct ADSC transplantation in the injured rotator cuff decreases inflammatory reactions and enhances tendon repair, thereby increasing tensile strength of injured tendon and shortening its recovery time. Since ADSCs possess an anti-inflammatory effect as well as immunomodulatory ability, type 1 diabetes mellitus (T1DM), which results from two abovementioned pathogeneses, is therefore a good candidate for clinical trials using ADSCs. Lin et al. review the current status of ADSC trial therapy for T1DM. Most often, these ADSCs are transfected with paired box 6 for insulin production, and the preliminary results show that this application of ADSCs is feasible and safe.
Lin et al. also propose a clinical trial to study the use of ADSCs to treat liver cirrhosis. They provide details of planned cell isolation, transplantation, and follow-up in six patients.
Stem Cell Therapy in Liver, Heart, and Immune Diseases
iPSCs from dental pulp-derived fibroblasts have been studied in treating acute hepatic failure animals by implanting into damaged liver with the hepatocyte-like cells differentiated from iPSCs. Chiang et al. demonstrated that the combination administration of iPSC-derived hepatocyte-like cells and control-released hydrogel of hepatocyte growth factor enhances engraftment of implanted cells and benefits liver regeneration via the molecular mechanisms of antioxidants and antiapoptotic effects.
Regarding myocyte protection in myocardial infarction, the protecting effect on myocytes under high-glucose and hypoxic conditions was studied in ESC-derived cardiomyocytes by Huang et al. They found that B-cell CLL/lymphoma 2 adenovirus E1B 19-kDa interacting protein (BNIP3) plays an important role in the hypoxic and hyperglycemic apoptosis of cardiomyocyte after hypoxic and hyperglycemic injury. Salvianolic acid B can effectively suppress the expression of BNIP3 and protect cardiomyocytes from being damaged.
Dendritic cells (DCs) play an important role in skin contact hypersensitivity via cytokines and T-cell proliferation. Fu et al. studied the effects of irisflorentin on mouse bone marrow-derived DCs in vitro and in vivo. They found that irisflorentin decreases the proinhibitory cytokine production of DCs, as well as proliferation of T-cells, thereby suppressing delayed skin hypersensitivity in mice.