Regenerating CNS white matter using induced pluripotent stem cells - Periventricular leukomalacia (PVL) is the leading cause of neurologic morbidity in premature infants leading to cerebral palsy and cognitive problems. The major neuropathologic hallmark of PVL is focal and diffuse periventricular white matter injury, featured by depletion of premyelinating oligodendrocytes (OLs) and myelination disturbances. No effective treatment for PVL is available. Recently, developing cell therapies for neonatal brain injury has gained increasing support. Our lab has identified PVL research as a strategic area of focus for our research program. Our long-term goal is to determine potential stem cell based therapeutic strategies for PVL. Accumulative studies indicate the therapeutic potential for neonatal hypoxic-ischemic injury with transplantation of different stem/progenitor cell preparations. It is prerequisite to derive cells in high purity and homogeneity for developing cell therapies. However, there is currently a common difficulty in obtaining homogenous stem/progenitor cells for transplantation studies and future clinical use. Moreover, the optimal types of cells for transplantation remain unclear. Studies in human tissues and in animal models of PVL showed that there is no lack of oligodendroglia progenitor cells (OPCs), because their proliferation is increased after PVL injury, but their maturation is largely delayed. Cell death is mainly seen in pre- myelinating OLs, but not in neurons. Hence, neuronal progenitors and OPCs may not be the optimal candidates in the PVL injury. Based on our preliminary data, here we propose to develop an astroglia-based cell therapy for neonatal brain injury. Our recent work has led to successful generation of immature astroglia from human embryonic stem cells (hESCs) in high homogeneity and purity (> 95%). We further demonstrated that transplantation of the hESC-derived astrocytes exhibited strong neuroprotective effects both in vitro and in vivo. Astrocytes are increasingly recognized as a crucial player in the myelination process during development and remyelination process after injury. We have been working on generation of human induced pluripotent stem cells (hiPSCs) from fibroblasts and their differentiation into OPCs for myelin regeneration and repair. A main advantage of hiPSCs with respect to hESCs is that they are an unlimited source of isogenic cells that might not be subjected to immune-rejection after transplantation. We have applied our efficient astroglial differentiation protocol o hiPSCs and generated hiPSC-derived immature astroglia. Our preliminary observation indicated that hiPSC-derived immature astrocytes promoted the maturation of OPCs into myelinating oligodendrocytes in vitro. Building upon these previous and preliminary results, we propose to examine whether transplantation of hiPSC-derived astrocytes promotes remyelination after neonatal brain injury in our established mouse PVL model, and the underlying mechanisms will also be explored. This novel study may lead to a new hiPSC-derived astroglia-based cell therapy for PVL, and will also provide new insight into the interaction between OLs and astrocytes, a previously understudied area of investigation. The scientific knowledge to be acquired through this project is of likely benefit to the development of stem cell based therapeutic strategies for treating human neurological disorders such as PVL.
Perinatal hypoxic-ischemic injury to developing oligodendroglia and central nervous system myelin is a primary cause of white matter pathology in the immature brain, termed periventricular leukomalacia (PVL), leading to the development of cerebral palsy (CP) in premature infants, a devastating life-long condition with no cure. In the U.S. alone, over 56,000 babies are born very prematurely annually, of whom ~10% develop CP. The economic and social impacts are huge. Here we seek to test an approach of using human induced pluripotent stem cells (iPSCs), to investigate the utility of these cells for oligodendroglal regeneration and myelin repair, and to develop an iPSC-based approach to help realize the promise of autologous cell-based stem cell therapy for preterm brain injury. A major goal of current human pluripotent cell research is to develop methods to differentiate stem cells into specific lineage cells and study their biology in clinically relevant animal models of human disease in vivo. Development of iPSC-based therapeutic strategies that can promote remyelination after premature brain injury will likely have significant translational potential and impact. The proposed research has important research and medical implications for human oligodendroglial development and myelin disorders.
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