Human stem cell-derived models of the blood-brain barrier and related tissues
Our broad research goal is to use human pluripotent stem cells (hPSCs) to engineer improved, multicellular in vitro models of the blood-brain barrier (BBB)/neurovascular unit and related tissues. Such models are useful in (1) screening small molecule and protein drugs for their ability to cross the BBB and enter the central nervous system (CNS), (2) interrogating signaling and cell-cell interactions important in human BBB development, and (3) studying the molecular mechanisms underlying CNS diseases through the use of patient-specific induced pluripotent stem cells. Within this framework, my effort has been focused in two areas. First, we have recently developed a method to differentiate brain pericyte-like cells from hPSC-derived neural crest stem cells. Brain pericytes are necessary for BBB development and maintenance. We are using this system to understand a putative role for Hedgehog signaling in the differentiation or function of neural crest-derived pericytes in the context of brain angiogenesis and barriergenesis. Second, we have refined methods for derivation of peripheral neurons and Schwann cells (glia of the peripheral nerves) also from hPSC-derived neural crest stem cells. We have hypothesized that, in analogy to the necessity of various CNS cell types in establishing the BBB, peripheral neurons or Schwann cells play roles in development of the endothelial blood-nerve barrier. We are co-culturing these cell types with hPSC-derived endothelial cells to determine their roles in regulating endothelial phenotypes.