LAR and PTPσ receptors are negative regulators of oligodendrogenesis and oligodendrocyte integrity in spinal cord injury
LAR and PTPσ receptors are negative regulators of oligodendrogenesis and oligodendrocyte integrity in spinal cord injury
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DOI：
10.1002/glia.23533
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发表时间：
2019-01-01
期刊：
影响因子：
6.2
通讯作者：
Karinni-Abdolrezaee, Soheila
中科院分区：
文献类型：
--
作者：
Dyck, Scott;Kataria, Hardeep;Karinni-Abdolrezaee, Soheila
脊髓损伤（SCI）后，成熟少突胶质细胞群体经历大量细胞死亡；促进它们的保存和替换是保护受损脊髓轴突完整性和白质修复的可行策略。基质硫酸软骨素蛋白聚糖（CSPGs）的显著上调被证明对内源性修复过程构成障碍，靶向CSPGs可改善脊髓损伤后的功能恢复。然而，CSPGs抑制作用的细胞和分子机制在很大程度上仍未明确。CSPGs特异性信号受体、白细胞共同抗原相关（LAR）和蛋白酪氨酸磷酸酶（PTP sigma）的调节使我们能够揭示CSPGs在SCI中调节少突胶质细胞的作用和机制。本研究在临床相关的大鼠挫伤/压缩性脊髓损伤模型中利用特异性功能阻断肽，我们证明抑制PTP sigma和LAR受体可促进内源性前体细胞的少突胶质细胞形成，减轻caspase 3介导的成熟少突胶质细胞死亡，并保存髓磷脂。在平行的体外系统中，我们已经揭示了CSPGs直接诱导神经前体细胞和少突胶质细胞祖细胞群体的凋亡，并限制它们对少突胶质细胞分化、成熟和髓鞘形成的能力。CSPGs的这些负面作用是通过激活LAR和PTP sigma受体以及下游的Rho/ROCK途径介导的。因此，我们已经确定了PTP sigma和LAR在调节损伤成人脊髓少突胶质细胞分化和凋亡中的新抑制作用，以及优化脊髓损伤后内源性细胞替代的新可行治疗策略。
Following spinal cord injury (SCI), the population of mature oligodendrocytes undergoes substantial cell death; promoting their preservation and replacement is a viable strategy for preserving axonal integrity and white matter repair in the injured spinal cord. Dramatic upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) is shown to pose an obstacle to endogenous repair processes, and targeting CSPGs improves functional recovery after SCI. However, the cellular and molecular mechanisms underlying the inhibitory effects of CSPGs remain largely undefined. Modulation of CSPGs specific signaling receptors, leukocyte common antigen-related (LAR), and protein tyrosine phosphatase-sigma (PTP sigma) allows us to uncover the role and mechanisms of CSPGs in regulating oligodendrocytes in SCI. Here, utilizing specific functionally blocking peptides in a clinically relevant model of contusive/compressive SCI in the rat, we demonstrate that inhibition of PTP sigma and LAR receptors promotes oligodendrogenesis by endogenous precursor cells, attenuates caspase 3-mediated cell death in mature oligodendrocytes, and preserves myelin. In parallel in vitro systems, we have unraveled that CSPGs directly induce apoptosis in populations of neural precursor cells and oligodendrocyte progenitor cells and limit their ability for oligodendrocyte differentiation, maturation, and myelination. These negative effects of CSPGs are mediated through the activation of both LAR and PTP sigma receptors and the downstream Rho/ROCK pathway. Thus, we have identified a novel inhibitory role for PTP sigma and LAR in regulating oligodendrocyte differentiation and apoptosis in the injured adult spinal cord and a new feasible therapeutic strategy for optimizing endogenous cell replacement following SCI.