Myelin basic protein (MBP) presented in the spinal cord niche, but not the brain niche, causes the release of an inhibitory factor that regulates neural precursor cell kinetics and oligodendrogenesis. Hence, regionally distinct niches along the neuraxis respond differently to the same protein (MBP) and regulate cell behavior.
Abstract
Neural stem and progenitor cells (collectively termed neural precursor cells [NPCs]) are found along the ventricular neuraxis extending from the spinal cord to the forebrain in regionally distinct niches comprised of different cell types, architecture, and cell‐cell interactions. An understanding of the factors that regulate NPC behavior is critical for developing therapeutics to repair the injured central nervous system. Herein, we demonstrate that myelin basic protein (MBP), the major cytoplasmic protein constituent of the myelin sheath in oligodendrocytes, can regulate NPC behavior. Under physiological conditions, NPCs are not in contact with intracellular MBP; however, upon injury, MBP is released into the neural parenchyma. We reveal that MBP presented in a spinal cord niche is inhibitory to NPC proliferation. This inhibitory effect is regionally distinct as spinal cord NPCs, but not forebrain‐derived NPCs, are inhibited by MBP. We performed coculture and conditioned medi a experiments that reveal the stem cell niche is a key regulator of MBP's inhibitory actions on NPCs. The inhibition is mediated by a heat‐labile protein released by spinal cord niche cells, but not forebrain niche cells. However, forebrain NPCs are also inhibited by the spinal cord derived factor as revealed following in vivo infusion of the spinal cord niche‐derived conditioned media. Moreover, we show that MBP inhibits oligodendrogenesis from NPCs. Together, these findings highlight the role of MBP and the regionally distinct microenvironment in regulating NPC behavior which has important implications for stem cell‐based regenerative strategies.
© AlphaMed Press 2021
Significance Statement
Neural precursor cells (NPCs) reside in regionally distinct niches in the central nervous system (CNS). The niche regulates NPC behavior in homeostatic and injury conditions. This study shows that myelin basic protein (MBP), a major constituent of myelin sheaths in the CNS, regulates NPC behavior in a niche dependent fashion. In vitro and in vivo studies reveal that MBP presented in the spinal cord niche, but not the brain niche, results in the release of a protein that inhibits NPC proliferation and oligogenesis. Hence, regionally distinct niches respond differently to the same protein (MBP), by releasing factors that regulate NPCs throughout the CNS.
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