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Niche-derived Factors Modulate Inhibitory Responses of NSCs to Myelin Basic Protein Exposure

Review of “Niche‐dependent inhibition of neural stem cell proliferation and oligodendrogenesis is mediated by the presence of myelin basic protein” from STEM CELLS by Stuart P. Atkinson

While on the search for factors that regulate the behavior of neural stem cells (NSCs) in response to injury or disease, researchers led by Nishanth Lakshman and Cindi M. Morshead (University of Toronto, Toronto, Ontario, Canada) demonstrated that extracellular myelin basic protein (MBP), an essential structural component in the formation of mature myelin in the central nervous system [1], inhibited the differentiation of spinal cord-derived NSCs without affecting survival [2] (See their STEM CELLS article for more!). While MBP normally helps to form the myelin sheath that wraps around neuronal axons [1], injury induces MBP release into the extracellular space, where it displays microenvironment-specific activity [3].

In their new STEM CELLS study [4], Lakshman et al. explored the potential role of MBP-associated inhibitory function in forebrain NSCs, which possess a distinct niche [5, 6]. The results of this exciting study highlight how regionally distinct microenvironments influence the impact of MBP on NSCs, a finding that may have important implications for the development of novel regenerative/reparative strategies.

The authors employed in vitro analysis of primary neurospheres derived from the forebrain and spinal cord of wild-type and MBP-deficient mice and confirmed these findings in animal models. They discovered that MBP inhibited the proliferation and oligodendrogenesis of brain and spinal cord NSCs when in the presence of spinal cord-derived conditioned medium; however, MBP had no inhibitory function on brain or spinal cord NSCs when in the presence of forebrain-derived conditioned medium. These findings suggested that a spinal cord microenvironmentally-derived factor may support the negative impact of MBP on NSCs after injury.

Encouragingly, the authors confirmed the existence of heat‐labile protein(s) released from spinal cord niche cells (but not forebrain niche cells) that mediated the inhibitory effects of MBP. Furthermore, the intraventricular infusion of spinal cord-derived conditioned medium into mice prompted a decrease in the proliferation of forebrain NSCs and their progeny, thereby confirming that regionally distinct NSC populations can respond to the spinal cord‐derived inhibitory factor.

The authors hope that their findings will help to delineate the factors and environmental conditions that influence NSC behavior, and in doing so, create a knowledge base that we can employ to induce neural regeneration through the modulation of exogenously-transplanted or endogenous neural stem or progenitor cells.

For more on the behavior of NSCs, the importance of niche-derived microenvironmental factors, and the development of novel regenerative/reparative strategies, stay tuned to the Stem Cells Portal!

References

  1. Harauz G and Boggs JM, Myelin management by the 18.5-kDa and 21.5-kDa classic myelin basic protein isoforms. Journal of Neurochemistry 2013;125:334-361.
  2. Xu W, Sachewsky N, Azimi A, et al., Myelin Basic Protein Regulates Primitive and Definitive Neural Stem Cell Proliferation from the Adult Spinal Cord. STEM CELLS 2017;35:485-496.
  3. Vassall Kenrick A, Bamm Vladimir V, and Harauz G, MyelStones: the executive roles of myelin basic protein in myelin assembly and destabilization in multiple sclerosis. Biochemical Journal 2015;472:17-32.
  4. Lakshman N, Bourget C, Siu R, et al., Niche-dependent inhibition of neural stem cell proliferation and oligodendrogenesis is mediated by the presence of myelin basic protein. STEM CELLS 2021;39:776-786.
  5. Fuentealba LC, Obernier K, and Alvarez-Buylla A, Adult Neural Stem Cells Bridge Their Niche. Cell Stem Cell 2012;10:698-708.
  6. Hugnot JP and Franzen R, The spinal cord ependymal region: a stem cell niche in the caudal central nervous system. Frontiers in Bioscience (Landmark Edition) 2011;16:1044-59.