Alpha-MSH modulates hippocampal neural precursor cell proliferation and differentiation

LILA CARNIGLIA; JULIETA SABA; DELIA RAMÍREZ; JUAN TURATI; JULIETA RUDI; FEDERICO LÓPEZ COUSELO; CARLA CARUSO; DANIELA DURAND; MERCEDES LASAGA

Porto

Congreso; XIV European Meeting on Glial Cells in Health and Disease; 2019

Network Glia

Hippocampal neurogenesis is essential for learning and memory. Neural precursor cells (NPCs) in the subgranular zone of the hippocampal dentate gyrus proliferate and differentiate into either glial cells or dentate granule cells, which eventually may integrate into the hippocampal neural circuitry. Melanocortins are neuropeptides derived from the posttranslational cleavage of pro-opiomelanocortin (POMC) which signal through five known melanocortin receptors (MCR). In the hippocampus, there is a well described POMC-MC4R circuit. The melanocortin alpha-melanocyte-stimulating hormone (MSH) improves learning, memory, neuronal survival and plasticity in models of neuroinflammation, brain ischemia and Alzheimer´s disease, and is a mitogen for growth factor-deprived adult rat subventricular zone neural stem cells. Here, we studied the effect of the synthetic melanocortin analog NDP-MSH on rat hippocampal NPC proliferation and differentiation, as well as its ability to modulate phagocytosis of apoptotic neural cells by hippocampal microglia.For this, postnatal hippocampal NPCs were propagated in vitro as neurospheres. Cells were dispersed and cultured without growth factors to allow for differentiation. NDP-MSH was added on days 0 and 3. After 6 days in culture a large proportion of NPCs became quiescent, evidenced by loss of nuclear Ki-67 expression. Treatment with NDP-MSH prevented the exit from cell cycle, increasing the proportion of Ki-67+ cells, particularly Ki-67+/Nestin+ cells (putative type-1 and type-2 proliferative precursors). Also, NDP-MSH promoted cell proliferation evidenced by increased proportion of BrdU positive nuclei. In turn, there was a decrease in the proportion of GFAP+/Ki-67- cells (putative astrocytes or quiescent type-1 precursors) and in the NS-1+ population (oligodendrocytes). Finally, postnatal hippocampal microglia were cultured and treated with or without NDP-MSH for 24 h. Simultaneously, a neuronal cell line (ST14A-Q120) was exposed to the pro-apoptotic agent 3-nitropropionic acid for 24 h. Neural cells were then stained with propidium iodide, collected and plated onto the microglial cell layer and phagocytosis of dead cells was assessed 1 h. later under a fluorescence microscope. Treatment with NDP-MSH increased the phagocytic capacity of microglial cells.In conclusion, our studies suggest a role for alpha-MSH in modulating the hippocampal neurogenic niche by regulating NPC fate while acting on local microglia to promote clearance of dead cells.