Sunday, May 5, 2024
5/5/2024
The identification of postnatal neural stem cells is essential to understand neural development, adult neurogenesis and gliogenesis, and the origin of brain tumors. Neural stem cells (NSCs) have been identified as a subpopulation of ventricle contacting astroglial (B1) cells in the ventricular-subventricular zone (V-SVZ) of the adult rodent brain. Our recent work has shown that B1 cells give rise to a second population of V-SVZ astroglial (B2) cells that do not contact the ventricle. The function of B2 cells is not known, but it has been suggested that B2 cells could function as secondary NSCs in rodents. Whether similar NSCs exist in the V-SVZ of the postnatal human brain remains unknown. Our studies in humans have revealed an extensive migration and recruitment of new neurons in the anterior forebrain of children younger than 6 months of age. Interestingly, astroglial cells with B1-like (hB1) and B2-like characteristics are present in the walls of the lateral ventricles in the human brain. hB1 cells are present at birth, but rapidly disappear within the first five months after birth. During this period, a sub-ependymal ribbon of human B2-like (hB2) cells forms next to the lateral ventricle walls. Preliminary data show that these hB2 cells are distinct from parenchymal astrocytes, continue to proliferate postnatally and have marker expression similar to embryonic radial glial. Our hypothesis is that hB2 cells lose apical attachment with the ventricle, but retain neural stem cell (NSC) properties to generate new neurons in the infant human brain. We hypothesize that this transformation of hB1 to hB2 cells is similar to the apical-basal transition that occurs in mice as B1 cells give rise to B2 cells, and that these secondary mouse (relay) progenitors retain NSC functions. Our objective is to characterize mouse and human B2 cells, trace their origin and determine if they have NSC properties. We propose three specific aims: Aim 1: We will use single cell genomics and high-resolution light and electron microscopy to define morphological and transcriptomic profiles of mouse and human B2 cells. Aim 2: We will use selective labeling, cell purification and transplantation to determine the function of mouse B2 cells. Aim 3: We will purify human V-SVZ astrocytes and test their progenitor potential in vitro and by xenotransplantation into the adult mouse brain. This new knowledge will impact our understanding of human brain development and postnatal neurogenesis, aiding in the discovery of developmental origins of neurological disorders in children and adults. The precise identification of a new human cell type with neurogenic potential could also be key for regenerative medicine and to trace the origin of brain tumors.
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