Abstract
The 8th Pan Pacific Symposium on Stem Cells and Cancer Research (PPSSC) was held in Hsinchu, Taiwan, on April 11–13, 2015. The symposium focused on the following themes: Frontier in iPS Cell and Epigenetics, Targeting Stem Cells: Trials and Translation; Emerging Drug Targets in Development and Discovery; Cutting Edges of Stem Cell and Immune Modulation; Adipose-Derived Stem Cell Plasticity for Regenerative Medicine; and Stem Cell Technology for Neurodegenerative Diseases. In this special issue, we highlight these topics in several original research and review articles regarding basic stem cell or immune cell research and clinical trials from this PPSSC meeting.
Induced Pluripotent Stem Cells (iPSCs): Induction and Applications
In order to investigate the pathogenesis of diseases, iPSCs induced from disease models are frequently adopted for genetic or biomarker studies. Katayama et al. found that the prairie vole (pv) was a good model for studying social behavior, which involves the oxytocin signaling pathway. The researchers generated high-quality iPSCs from this animal by constructing a polycistronic reprogramming vector [including octamer-binding transcription factor 3/4 (Oct3/4), sex-determining region Y box 2 (Sox2), Kruppel-like factor 4 (Klf4), c-Myc, Lin28, and Nanog] and conducted further genetic analysis. The results demonstrated that the pv-iPSC paradigm could be a useful tool for future studies of social behavior. Autologous cell therapy by using iPSC-derived progenitor cells has been applied for treatment of macular degeneration in clinical trials in Japan. Wei et al. investigated their safety and therapeutic effects in rats modeled with traumatic brain injury (TBI). They found that the mouse iPSC-derived neural progenitor cells subjected to hypoxic conditions (HP-IPSC-NPCs) and then implanted directly into the brain improved performance on behavior tests and did not appear to have any adverse effects. The recovery was significantly greater in the HP-IPSC-NPC group than the normoxic group, as indicated by higher levels of oxytocin-related genes and receptors in the hypoxic group.
Immune cell therapy is recognized as a possible, powerful tumoricidal therapy, of which chimeric antigen receptor (CAR) T-cell therapy is an example. iPSCs may also be induced to become immune cells. Haque et al. studied the effects of the engineered pluripotent stem cells in melanoma therapy. They found that they could generate apoptosis-resistant T cells from iPSCs, which resulted in highly reactive, antitumorigenic T cells.
Mesenchymal Stem Cells: Production, Application in Stroke, Myocardial Infarction, Cartilage Degeneration, And other Clinical Trials
Mesenchymal stem cells (MSCs) are the most common type of stem cell used in clinical trials due to their record of safety once transplanted, ubiquity in the body, and multilineage differentiation capabilities. More than 493 trials were extensively reviewed, and their results were analyzed by Squillaro et al. These trials were conducted for a number of diseases, including graft-versus-host disease (GVHD), diabetes, stroke, and autoimmune diseases. The MSCs used in these trials were predominantly heterogeneous populations of cells isolated from various tissues including bone marrow, adipose tissue, and other tissues. The authors provided evidence of a dramatic increase in the number of clinical trials using MSC-based therapy in recent years and offered insight into possible mechanisms of action, limitations, and efficacy. Dezawa discussed a subpopulation of MSCs, known as multilineage-differentiating stress-enduring (Muse) cells that were first discovered in 2010. Muse cells comprise a large percentage of MSCs and can be isolated from a variety of mesenchymal tissues. Muse cells have pluripotent-like properties and can differentiate into cells of all three germ layers, including neural- and hepatocyte-like cells. They are particularly valued for their ability to migrate and integrate into damaged tissue.
In addition to cell transplantation, regulation of endogenous repair mechanisms is also an important therapeutic approach. Neurodegenerative conditions such as Huntington's disease and cerebrovascular diseases such as stroke are some of the leading causes of disability in the world, and cell therapy has been put forth as a possible method of tissue regeneration. Yu et al. describe methods to enhance endogenous stem cell production from the subventricular zone by exogenous factors including neurotrophic factors, hematopoietic growth factors, and magnetic stimulation, as well as enriched environments. In another review by Watson et al., the possibility of treating neurological conditions by stimulating endogenous repair mechanisms was further explored. The authors focused on the possible therapeutic benefits of exogenously delivered melatonin and other natural compounds as treatment alternatives for neurodegenerative conditions, with a particular emphasis on stroke. Yamashita and Abe reviewed their recent progress in the development of new and combined strategies for the treatment of stroke, thus underscoring the importance of a multifactorial approach to regenerative medicine.
MSC therapy for stroke may also be potentiated by preconditioning the MSCs prior to transplantation. Rather than employing the previously mentioned hypoxic preconditioning, Chi et al. tested the therapeutic effect of preconditioning of adipose tissue-derived stem cells (ADSCs) with ligustilide, a small molecule isolated from the herb Angelica sinensis, in a murine model of stroke. The results demonstrated that this therapeutic regimen produced better functional recovery of neurological deficits due to higher expression of stromal-derived factor-1 (SDF-1) and chemokine (C-X-C motif) receptor 4 (CXCR4) homing factors compared with control animals.
In addition to cell therapy, mitochondrial therapy has also been tested in stroke animals. Huang et al. investigated the potential beneficial effects of either transferring xenogenic mitochondria directly into ischemic rat brains or using intra-arterial infusion of the mitochondria via the femoral artery. They found that mitochondria injected directly into either the ischemic brain or the arteries significantly restored the motor performance of animals modeling a stroke. The molecular mechanisms underlying mitochondria-mediated neuroprotection should be explored further.
MSCs have also been applied for treatment of myocardial infarction (MI), and poor survival rates of transplanted MSCs in the infarct region were noted in a review by Peng et al. In spite of poor cell survival rates, therapeutic effects have been observed in preclinical and clinical studies of MSC transplantation for treatment of MI. The therapeutic effects have been attributed to molecular mechanisms related to modulation of inflammatory pathways. The authors presented a new mechanism; they discussed the tendency of transplanted MSCs to migrate to and become lodged in the extracardiac organs, such as the spleen and bone marrow, thereby promoting the transition of macrophages from the proinflammatory M1 subtype, to the anti-inflammatory M2 subtype.
Chang et al. evaluated the latest methods for chondrocyte differentiation of MSCs, focusing on the role of signal transduction in this process, and exploring the future direction of MSC application in treating osteoarthritis (OA). Alternatively, transplantation of progenitor cells may also be an option for various pathological conditions. Kagimoto et al. isolated cartilage progenitor cells from the ear perichondrium of primates. These perichondrial progenitor cells were cultured, expanded, and then transplanted into both an immunodeficient mouse and autologously into primates with craniofacial abnormalities. The researchers concluded that autologous transplantation of cartilage progenitors is promising for the treatment of craniofacial deformities or injuries.
Another source of cells with regenerative potential was studied by Eve et al. The researchers studied the effect of human umbilical cord blood (hUCB)-derived mononuclear cells (MNCs) for the treatment of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease due to a progressive degeneration of motor neurons in the brain and spinal cord, for which there is no known cure or substantive treatment. The researchers conducted an in vitro study using hUCB plasma to treat MNCs derived from the blood of ALS patients. Reduced apoptosis (caspase 3 levels) was observed in the plasma-treated MNCs, suggesting that hUBC plasma, which is rich in cytokines and growth factors, may be a future therapeutic option for ALS.
Peripheral Nerve Regeneration
Peripheral nerve regeneration is an important topic in neural repair. Yi et al. demonstrated that the novel microRNA, miR-sc3, can promote the proliferation and migration of primary Schwann cells. Yao et al. also explored the potential therapeutic options for repair of sciatic nerves by combining bone marrow mononuclear cells (BM-MNCs) and chitosan/silk fibroin scaffolds, referred to as tissue-engineered nerve grafts (TENGs). It was shown that the TENG-transplanted group had a better histological and functional recovery of the injured nerve compared to the control. These results may be related to the 2-week survival time of bone marrow mononuclear cells after nerve grafting.
This special PPSSC issue of Cell Transplantation highlights important topics in the milieu of stem cell and cancer research, and the information that may be gleaned from articles herein should serve to propel researchers forward. I would like to offer my sincere appreciation to those who contributed their valuable, multidisciplinary data and keen insights to this special issue and look forward to the 9th Pan Pacific Symposium on Stem Cells and Cancer Research in May of 2016.