Balakrishnan Anjali, Belfiore Lauren, Chu Tak-Ho, Fleming Taylor, Midha Rajiv, Biernaskie Jeff, Schuurmans Carol
Biological Sciences Platform, Sunnybrook Research Institute (SRI), Toronto, ON, Canada.
Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
Front Mol Neurosci. 2021 Jan 25;13:608442. doi: 10.3389/fnmol.2020.608442. eCollection 2020.
Peripheral nerve injuries arising from trauma or disease can lead to sensory and motor deficits and neuropathic pain. Despite the purported ability of the peripheral nerve to self-repair, lifelong disability is common. New molecular and cellular insights have begun to reveal why the peripheral nerve has limited repair capacity. The peripheral nerve is primarily comprised of axons and Schwann cells, the supporting glial cells that produce myelin to facilitate the rapid conduction of electrical impulses. Schwann cells are required for successful nerve regeneration; they partially "de-differentiate" in response to injury, re-initiating the expression of developmental genes that support nerve repair. However, Schwann cell dysfunction, which occurs in chronic nerve injury, disease, and aging, limits their capacity to support endogenous repair, worsening patient outcomes. Cell replacement-based therapeutic approaches using exogenous Schwann cells could be curative, but not all Schwann cells have a "repair" phenotype, defined as the ability to promote axonal growth, maintain a proliferative phenotype, and remyelinate axons. Two cell replacement strategies are being championed for peripheral nerve repair: prospective isolation of "repair" Schwann cells for autologous cell transplants, which is hampered by supply challenges, and directed differentiation of pluripotent stem cells or lineage conversion of accessible somatic cells to induced Schwann cells, with the potential of "unlimited" supply. All approaches require a solid understanding of the molecular mechanisms guiding Schwann cell development and the repair phenotype, which we review herein. Together these studies provide essential context for current efforts to design glial cell-based therapies for peripheral nerve regeneration.
由创伤或疾病引起的周围神经损伤可导致感觉和运动功能障碍以及神经性疼痛。尽管周围神经据称具有自我修复能力，但终身残疾却很常见。新的分子和细胞研究见解已开始揭示周围神经修复能力有限的原因。周围神经主要由轴突和施万细胞组成，施万细胞是产生髓磷脂以促进电冲动快速传导的支持性神经胶质细胞。成功的神经再生需要施万细胞；它们在损伤后会部分“去分化”，重新启动支持神经修复的发育基因的表达。然而，在慢性神经损伤、疾病和衰老过程中出现的施万细胞功能障碍，限制了它们支持内源性修复的能力，从而使患者的预后恶化。使用外源性施万细胞的基于细胞替代的治疗方法可能具有治愈作用，但并非所有施万细胞都具有“修复”表型，“修复”表型的定义为促进轴突生长、维持增殖表型以及使轴突重新髓鞘化的能力。目前有两种细胞替代策略被用于周围神经修复：前瞻性分离用于自体细胞移植的“修复”施万细胞，但受到供应挑战的阻碍；以及将多能干细胞定向分化或使可获取的体细胞谱系转化为诱导性施万细胞，具有“无限”供应的潜力。所有这些方法都需要深入了解指导施万细胞发育和修复表型的分子机制，我们将在本文中对此进行综述。这些研究共同为当前设计基于神经胶质细胞的周围神经再生疗法的努力提供了重要背景。
