Niche-dependent inhibition of neural stem cell proliferation and oligodendrogenesis is mediated by the presence of myelin basic protein

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 media 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.

RNA Profiling of Mouse Ependymal Cells after Spinal Cord Injury Identifies the Oncostatin Pathway as a Potential Key Regulator of Spinal Cord Stem Cell Fate

“…It remains unanswered why, compared to zebrafish, mammal ependymal cells generate mainly astrocytes, few oligodendrocytes, and no neurons after SCI. This could be due to astrocytic-fate determining factors expressed by these cells prior to injury such as SOX9 or NFIA transcription factors [ 6 ] or by structural proteins in the environment such as myelin basic protein [ 77 ]. In addition and reminiscent of the zebrafish situation [ 78 ], here we found evidence that their fate could be influenced by inflammatory cytokines provided by the environment, possibly microglia.…”

Adhesive, Stretchable, and Spatiotemporal Delivery Fibrous Hydrogels Harness Endogenous Neural Stem/Progenitor Cells for Spinal Cord Injury Repair

“…Among them, neurons are vital for reconstruction of the neural network and proper function. It has been reported that the majority of the endogenous or exogenous NSPCs in the injury site tend to differentiate into glial cells rather than neurons, resulting in limited success in functional recovery. , To solve this issue, various attempts have been made to alleviate the inhibitory microenvironment for improving neuronal differentiation in vivo . , In our previous studies, epidermal growth factor receptor (EGFR) neutralizing antibody was used for Col scaffold functionalization to block EGFR-related signaling triggered by myelin-associated proteins. , The functionalized Col scaffolds improved neuronal differentiation of exogenous NSPCs embedded in the scaffolds and promoted functional recovery of SCI rats. In a follow-up study, we demonstrated that EGFR neutralizing antibody functionalized Col scaffolds induced neurogenesis of endogenous NSPCs, leading to locomotion recovery .…”

“…57,58 To solve this issue, various attempts have been made to alleviate the inhibitory microenvironment for improving neuronal differentiation in vivo. 59,60 In our previous studies, epidermal growth factor receptor (EGFR) neutralizing antibody was used for Col scaffold functionalization to block EGFR-related signaling triggered by myelin-associated proteins. 35,61 The functionalized Col scaffolds improved neuronal differentiation of exogenous NSPCs embedded in the scaffolds and promoted functional recovery of SCI rats.…”

Regulating Endogenous Neural Stem Cell Activation to Promote Spinal Cord Injury Repair

“…Oligodendrocytes are the myelinating cells in the CNS. While the presence of mature oligodendrocytes has not been demonstrated to directly affect NSC behavior, exposure to oligodendrocyte-associated proteins released following injury/disease has been shown to have profound effects on their behavior [ 48 , 182 ] Following SCI, oligodendrocytes undergo rapid cell death which persists for up to three months post-injury [ 183 ]. One of the most abundant proteins comprising mature is myelin basic protein (MBP).…”

“…Normally cytoplasmic is released into the microenvironment following SCI [ 184 ]. Both in vitro and in vivo studies have shown that MBP is inhibitory to NSC proliferation and NSC-derived oligodendrogenesis [ 48 , 182 ]. Most interesting, the observed inhibition is not a direct effect of MBP on NSCs, but instead is due to the indirect effect of MBP on spinal cord PVZ cells, which then release an unidentified factor that acts on NSCs [ 46 , 176 ].…”