The embryonic stem cells (ESCs), featured by the capability to both self-renew and differentiate into each cell type, hold great promise for regenerative medicine. However, ethical concern and immune rejection are the two major hurdles for the clinical development of ESCs. Promisingly, the induced pluripotent stem cell (iPSC) is believed to be able to get across those barriers. It provides an unprecedented opportunity to model human disease, identify new therapeutic targets and test new therapies, potentially provide autologous cell resources in regenerative medicine without concerning the immune rejections led by major histocompatibility complex (MHC) restriction. Among various diseases, one of the most popular trends in using differentiated iPSC derivatives is the study of the nervous system functioning and therapy of neurodegenerative diseases. At present, iPSC derivatives have been developed into commercial products, and there are two mainstream products, different cellular secretion components and numerous cells derived from human iPSC.
Stem cell differentiation involves the changing of a cell to a more specialized cell type and the switch from proliferation to specialization. This includes a succession of alterations in cell morphology, membrane potential, metabolic activity and responsiveness to certain signals. Under this circumstance, iPSCs and cells derived from iPSC can secret various kinds of components when cultured, such as growth and differentiation factor, vascular endothelium growth factor, transforming growth factor, platelet-derived growth factor and so forth. These factors in turn affect the growth and differentiation of cells.
Besides, secreted cellular components can be applied to an autologous therapy by simulating endogenous repair. Micro-vesicles such as exosomes secreted from the iPSC-derived cardiomyocytes exert protective effects by transferring the endogenous molecules to salvage the injured neighboring cells by regulating apoptosis, inflammation, fibrosis, and angiogenesis. Thus, the exosomes generated from patient-specific iPSC derivatives are expected to provide higher therapeutic specificity, quality control, ease of production, and safety than stem cell transplantation.
iPSCs, derived by ectopic expression of reprogramming factors in somatic cells, can potentially provide unlimited autologous cells for regenerative medicine. In theory, the autologous cells derived from patient iPSCs should be immune tolerant by the host without any immune rejections. The genetic and epigenetic defects induced by reprogramming are differentially presented during the iPSC differentiation. The iPSC descendents without presentation of the defects during differentiation are not immunogenic. Tissues with pronounced defects are immunogenic but may have a distinct destiny. Induced pluripotency leads to genetic and epigenetic defects in iPSCs such as genomic DNA mutation, abnormal genomic DNA methylation and gene expression, copy number variation and chromosomal aneuploidy.
Fig.3 Differential immunogenicity of iPSC derivatives. (Cao, 2014)
Given the high variability across iPSC lines and their differentiated derivatives in terms of their epigenetic status, tumorigenic and immunogenic potential, differentiation capacity, batch variability, the existence of heterogeneous populations and/or non-relevant cells such as contaminating cell, the clinical outcome of the cell replacement therapy highly relies on the acceptable quality and safety standards of these products.
Reference
For Research Use Only. Not For Clinical Use.
