Abstract
The Pan Pacific Symposium on Stem Cells and Cancer Research (PPSSC) was held in Hsinchu, Taiwan on April 12–15, 2013. The main themes for this meeting were stem cells, translational therapy, and new drug development. Among them, 24 topics were highlighted as described below.
Stem Cell Preparation (Modification and Isolation)
Stem cells can be isolated from tissue using a variety of procedures. Methods that improve the recovery ratio of stem cells during the isolation process and also ensure that their stemness is maintained are crucial. Chan et al. describe various such methods for isolating human mesenchymal stem cells (MSCs). In addition, Young compares the cell quality of umbilical cord blood frozen by either plasma-depleted or red blood cell-depleted methods. Clinical transplantation results in oncology and hematology patients of cells obtained from both methods and they have shown a better outcome using the plasma-depleted method due to its better yield of total nucleated cells.
It is also important to consider the genetic and epigenetic stabilities of the stem cells during preparation. Factors that affect these stabilities are reviewed by Rajamani et al. including extrinsic factors, such as growth supplements, oxygen tension, passage techniques, etc., and intrinsic factors, which are much more unpredictable and uncontrollable.
In recent years, the ability to use transcription factors to generate neuronal cells and neural stem cells from somatic cells has come to light. Yamashita and Abe reviewed this and how these modified cells can then be applied for transplantation therapies.
Mechanisms of Tissue Regeneration
Tissue regeneration can occur via a number of ways, but first of all, it is important to understand what exactly is going wrong in any disease state, for example, the polyglutamine (polyQ) diseases. The mutant polyQ proteins are aggregated in the degenerated neurons in diseases such as spinocerebellar ataxias, Huntington's disease, spinal and bulbar muscular atrophy, which can be partially rescued by stem cell therapy, as reviewed by Fan et al.
A major disease in which the mechanisms of action are unclear is cancer. Stem cells could contribute to cancer both causatively (cancer stem cells) and as a potential treatment. Chiu et al. describe the roles of normal stem cells and deregulated let-7 expansion in tumorigenesis and discuss the future application of let-7 in regenerative medicine and oncology.
One form of tissue regeneration that occurs continuously, even under normal conditions, is neurogenesis and dendritic/synaptic remodeling. One major area of the brain that is known to readily undergo remodeling is the hippocampus. Yau and So provide an overview of hippocampal plasticity and Yau et al. report on the possible roles of exercise and stress steroids to synaptic remodeling.
Translational Stem Cell Therapy
Numerous different stem cells have been obtained, and numerous animal studies have been performed to determine their optimal characteristics and explore how this may affect their potential to treat a number of different disorders. For example, the unique stemness and immunological properties of umbilical cord blood means that this a good allogeneic source of stem cells, which can differentiate into hematopoietic, epithelial, endothelial, and neural tissues, meaning that they could have regenerative applications as a treatment for a number of different disorders, as reviewed by Jaing. As well as the blood, the umbilical cord is also a source of stem cells. One such cell is cord lining stem cells. Lim and Phan review their current application in difficult-to-heal human wounds and persistent epithelial defects of the cornea. Owing to the characteristics of its rapid and inexpensive cell activation and expansion for clinical therapies, they propose its future application in heart and liver regeneration.
One of the most commonly studied stem cells is that of the bone marrow-derived MSCs. Their applicability for treating musculoskeletal diseases is reviewed by Wei et al. These cells could be applied to diseases of bone fracture, bone defects, focal chondral lesions, osteoarthritis, spinal diseases, and tendon injuries. MSCs have also been used to treat cardiac muscle. Translational clinical phase I/II trials in ischemic heart disease using MSCs have been conducted worldwide. Chou et al. review the results of these clinical trials and their possible molecular mechanisms involving transdifferentiation and the niche in myocardial tissue and highlight the bottleneck of MSC cardiac therapy.
Ideally, any cell therapy for the central nervous system could be applied in the least invasive manner. However the blood–brain barrier is one of the limiting factors for transplanted circulating stem cells entering the central nervous system. Gonzales-Portillo et al. provide an overview of mannitol-enhanced delivery of stem cells and their growth factors across the blood–brain barrier and propose the application for stroke and neonatal cerebral palsy.
In addition to the previously mentioned stem cell sources, one that is increasingly being studied is adipose tissue. Chan et al. review the effects of adipose-derived stem cell therapy in chronic stroke animals, in which molecular mechanisms for angiogenesis and neurogenesis are discussed, especially the creation of homing factors in chronic injured tissue by stem cell transplantation as the key mechanism in treating chronic stroke. Chan et al. discuss the translational test of adipose tissue-derived stem cell therapy in neurological degenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's, Alzheimer's, and Huntington's diseases. The combination of intracerebral and intravenous administration of stem cells for locally enhancing the creation of homing factors in the central nervous system (CNS) is also addressed.
Additionally, the role of endogenous, rather than transplanted, stem cells in CNS regeneration should also be considered. One possible means to enhance stem cell mobilization and proliferation in the CNS is acupuncture, as reviewed by Ho et al. The contribution of acupuncture as a treatment for stroke, depression, Parkinson's, and Alzheimer's diseases is also discussed. Olfactory ensheathing cells (OECs) guide olfactory axonal growth and help connect both the peripheral and central nervous systems and have been applied to treat CNS diseases. Chou et al. provide a systemic review for OEC properties and its therapeutic effects on spinal cord and peripheral nerve injury, stroke, and neurological degenerative diseases. Regarding spinal cord regeneration, Young provides a systemic review from basic to clinical, from molecular mechanism to tissue functional regeneration. Young concludes that the signal pathway of phosphatase and tensin homolog/protein kinase B/mammalian target of rapomycin (PTEN/AKT/mTOR), cAMP, and glycogen synthase kinase 3-β (GSK3b) play a key role in the corticospinal tract regeneration.
One disorder that everyone will eventually succumb to is aging. The level of circulating cluster of differentiation 34-positive (CD34+) stem cells has been proposed as one of the biomarkers of aging. Ho et al. have studied the effect of Tai Chi Chuan, one of the traditional Chinese Kung Fu, on the circulating levels of CD34+ stem cells. They found that in a long-term Tai Chi Chuan (more than 1 year)-practicing group of young adults, significant increases in the level of circulating CD34+ stem cells compared to an active comparison group (brisk walking) were observed, suggesting that Tai Chi Chaun may be a good choice of exercise for longevity.
Tissue engineering for producing clinical-grade tissue for therapy have been reported in several cases. Decellularization and recellularization processes, such as the key steps for the tissue engineering of extracellular matrix in decellularization, and the usages of various stem cells in recellularization, were reviewed by Fu et al.
New Drug Development and Tumor Stem Cells
Osteoporosis is one of the major problems of body aging. Hsu and Chang highlight a new molecular target, interleukin (IL)-20, for treating osteoporosis. The molecular mechanisms of promoting inflammation, angiogenesis, and osteoclastogenesis by IL-20 are described, and effects of IL-20 monoclonal antibody on osteoporosis, arthritis, and breast tumor-induced osteolysis are reviewed. Rejection in allograft is another important issue. Fu et al. found that dryocrassin, a natural small molecular compound, can modify dendritic cell function, including reducing the secretion of tumor necrosis factor-α, IL-6, IL-12, and inhibiting T-cell proliferation. Dryocrassin may be beneficial in transplant rejection by its immunosuppressive effect.
Natural small molecular chemicals, such as salvianolic acid B (Sal B), may serve as a leukemia-induced factor (LIF) for maintaining self-renewing function of stem cells in culture system. Sal B can maintain stem cell pluripotency and increase cellular proliferation rate by activating Janus kinase 3/signal transducer and activator of transcription 3 (Jak2/Stat 3) in combination with the epidermal growth factor receptor–extracellular signal-regulated kinase 1/2 (EGFR–ERK1/2) pathways. Liu et al. propose that Sal B can therefore be used as a LIF replacement due to its low cost.
The contribution of tumor stem cells to cancer is still under investigation, though they are believed to be a key contributing factor for tumor relapsing and becoming drug and radioresistant. A new target for inhibiting tumor stem cells was proposed by Lee et al., who found that CD133+ subpopulation of tumor stem cells derived from atypical teratoid/rhabdoid tumors (ATRT) expresses low levels of the microRNA miR142-3p. Overexpression of miR142-3p inhibits its proliferation and tumorigenicity and prolongs the survival time in orthotropic-transplanted nude mice. Novel miRNA-based strategies may therefore be one of the new targets for treating tumor stem cells.