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Induction of hematoendothelial and neurovascular lineages using human pluripotent stem cells


The regenerative capabilities of human pluripotent stem cells (hPSCs) have transformed the landscape of translational research, providing alternative approaches to treating devastating diseases. hPSCs are defined by the ability to self-renew and differentiate into all three germ layers: ectoderm, mesoderm, and endoderm, and have the potential to give rise to any cell type in the human body. The purpose of this research is to harness the differentiation potential of hPSCs to better understand the development of mesodermal and neural crest-derived blood-brain barrier pericytes of the central nervous system (CNS) and mesodermal-derived hematopoietic stem cells (HSCs) that give rise to the blood and immune systems. A single HSC has the potential to give rise to the entire blood system. However, the induction of definitive hematopoietic progenitors, which display multipotency and can home and engraft to the bone marrow upon transplantation, has proven difficult. Thus, the goal of this project is to develop a differentiation protocol to generate definitive hematopoietic progenitors from hPSCs. This work was later adapted to make neurovascular cells of the CNS, with a particular focus on pericytes.

Pericytes are a mural cell found in close association with endothelial cells and are essential to vascular maturation and maintenance. Pericytes have diverse developmental origins and are found in a wide variety of tissues and organs throughout the body. In particular, pericytes are a major component of the blood-brain barrier (BBB), which is also comprised of endothelial cells and astrocytes. The BBB is a selectively permeable network of blood vessels that protects and maintains homeostasis of the central nervous system (CNS) by regulating the transportation of molecules into and out of the brain. Dysfunction of the BBB has been implicated in the progression of Alzheimer’s Disease (AD), in which the accumulation of neurotoxic plaques of beta amyloid (Aβ) peptides leads to neuronal loss, cognitive decline, and, ultimately, death. However, the mechanism of BBB breakdown in AD, including the disrupted interactions between the three cell types, are not well understood. While protocols to generate astrocytes and brain endothelial cells from hPSCs exist, there are currently no protocols to create iPSC-derived CNS-specific pericytes. The primary focus of this work is to generate brain-specific pericytes from induced pluripotent stem cell (iPSC) lines created from patients bearing alleles for APOE3 or APOE4, which is the single greatest genetic risk factor for AD.

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