Increased generation of new neurons in the brain, upregulation of the process of neurogenesis, is an important goal for the field of regenerative medicine. It would likely improve brain function at all ages, but since neurogenesis declines with age as stem cell populations become less active, it would be of particular relevance to the aging brain. Thus researchers are looking for ways to influence the regulatory systems controlling quiescence versus activity in neural stem cells and progenitor cells, in order to override the natural response to the aged tissue environment and put them back to work.
In most mammals, neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ) continues during adulthood. In rodents and non-human primates, new neurons generated in the SVZ migrate to the olfactory bulb. In humans, on the other hand, the addition of new neurons to the olfactory bulb is likely negligible and new neurons produced in the SVZ migrate to the neighboring striatum. Growing evidence suggests that the decline in neurogenesis observed during aging in mammals is due to increased quiescence of neural stem cells (NSCs) and progenitors (hereafter progenitors refers to both NSCs and progenitors).
Studies in rodents have shown that adult NSCs arise from a population of quiescent radial glial cells that accumulate embryonically. Rather than being a static non-proliferating pool of cells, studies in rodents have demonstrated that they are a very dynamic population of cells that transit between proliferative and quiescent states. With aging progenitors become less plastic and remain mainly quiescent, which prevents depletion of the progenitor pool. The mechanisms that regulate quiescence of progenitors are just beginning to be unraveled.
We have previously identified CD271 as a marker expressed by progenitors of the aged human SVZ. The present study assesses the molecular identity of CD271-positive progenitors from the SVZ of the aged human brain at single-cell level and investigates a mechanism through which human progenitors could be maintained in a quiescent state. We identify the secreted frizzled-related protein-1 (SFRP1), an inhibitor of the Wnt signaling pathway, to be among genes whose expression changes over time. We demonstrate that inhibition of SFRP1 with a small molecule stimulates proliferation in vitro, in human iPSC-derived NSCs, and in vivo in early postnatal mice. Altogether, our work proposes a mechanism that maintains quiescence of progenitors of the human SVZ, which opens up future possibilities to stimulate NSCs of the human brain to promote repair.