As a central tenet of regenerative biology is that processes controlling tissue generation during development often control its regeneration, the basic and translational stem cell research we are pursuing critically bridges between the understanding of human neural development in heath and disease, and the development of stem cell regenerative medicine.
I) Microglia-based cell therapy. Alzheimer’s disease (AD) remains incurable and attempts to slow down the disease progression and cognitive decline often prove unsuccessful. There is an urgent need for new therapeutic strategies. In recent years, genome-wide association studies, whole genome sequencing, and gene-expression network analysis have implicated that immune networks play a significant role in AD (Efthymiou and Goate, 2017). These studies have also uncovered many AD risk genes that are primarily expressed by microglia, the brain-resident innate immune cells. Microglia are essential in maintaining brain homeostasis and health. However, in the context of AD, microglia lose their ability to provide normal neuroprotective functions and instead undergo various dysfunctional changes, including morphological alterations, impaired lipid metabolism, and transcriptional changes, all of which are frequently detrimental, leading to neurodegeneration and cognitive decline (Lewcock et al., 2020). Introducing healthy and functionally competent microglia or microglia-like cells as replacements of diseased microglia presents potential therapeutic avenues for AD treatment.
Jiang P, Jin M. Replacing microglia to treat Alzheimer’s disease. Cell Stem Cell. 2023;30(8):1001-3. doi: 10.1016/j.stem.2023.07.005.
II) Macroglia (astroglia and oligodendroglia)-based cell therapy. Astroglia, also called astrocytes, are a major cellular constituent of the central nervous system (CNS) and play crucial roles in brain development, function, and integrity. Increasing evidence demonstrates that astroglia dysfunction occurs in a variety of neurological disorders ranging from CNS injuries to genetic diseases and chronic degenerative conditions. These new insights herald the concept that transplantation of astroglia could be of therapeutic value in treating the injured or diseased CNS. Recent technological advances in the generation of human astroglia from stem and progenitor cells have been prominent. Currently, we focus on studying human astroglia development, developmental interactions between human astroglia and oligodendroglia, and establishing human PSC-derived astroglia therapies for treating myelin loss disorders, such as brain hypoxic-ischemic injury and multiple sclerosis, through promoting proliferation and maturation of resident oligodendroglia progenitor cells and further enhancing myelination or remyelination (Figure 2).
Representative publications (*co-corresponding author; #co-first author):
Jiang P*, Chen C, Liu XB, Pleasure D, Liu Y, Deng W*. Promoting Oligodendrogenesis by Human iPSC-derived Immature Astroglia via TIMP-1 Secretion. Cell Reports. 2016 May 10;15(6):1303-15.
Chen C, Chan A, Wen H, Chung SH, Deng W*, Jiang P*. Stem and progenitor cell-derived astroglia therapies for neurological diseases. Trends in Molecular Medicine. 2015 Nov;21(11):715-29.
Jiang P, Chen C, Liu XB, Selvaraj V, Liu W, Pleasure D, Liu Y, Li R, Deng W. Generation and characterization of spiking and non-spiking oligodendroglial progenitor cells from embryonic stem cells. Stem Cells.
Jiang P, Chen C, Wang R, Chechneva O, Chung SH, Liu Y, Rao M, Pleasure D, Zhang Q, and Deng W. Human embryonic stem cell-derived Olig2+ progenitors generate a subtype of astroglia with highly protective effects against ischemic brain injury. Nature Communications. 2013 Jul 23;4:2196.
Liu Y#, Jiang P#, Deng W., Olig gene targeting in human pluripotent stem cells for motor neuron and oligodendrocyte differentiation. Nature Protocols. 2011 May;6(5):640-55.