Deficiency of angiogenic and neurotrophic factors under long term diabetes is known to lead to Schwann cell degeneration, clinically manifested as Diabetic Neuropathy (DN). While the transplantation of exogenous allogenic Mesenchymal Stromal Cells (MSCs) has shown amelioration of DN through paracrine action, it is not known what functional changes occur in endogenous bone-marrow MSCs under chronic diabetes in terms of homing, migration and/or paracrine signalling with reference to the end-point clinical manifestation of Diabetic Neuropathy. We thus aimed at determining the changes in BM-MSCs under Type 1 Diabetes with respect to survival, self-renewal, oxidative status, paracrine activity, intracellular Ca²⁺ response and migration in response to pathological cytokine/chemokine, in reference to the time-point of decline in Nerve Conduction Velocity (NCV) in a rat model. Within one week of diabetes induction, BM-MSCs underwent apoptosis, and compromised their self-renewal capacity, antioxidant defence mechanism and migration toward cytokine/chemokine; whereas epineurial blood vessel thickening and demyelination resulting in NCV decline were observed only after three weeks. By two- and three-weeks post diabetes induction, BM-MSC apoptosis reduced and proliferative ability was restored; however, their self-renewal, migration and intracellular Ca²⁺ response toward pathological cytokine/chemokine remained impaired. These results indicate that T1D induced intrinsic functional impairments in endogenous BM-MSCs occur before neuropathy onset. This timeline of functional alterations in BM-MSCs also suggest that treatment strategies that target the bone marrow niche early on may help to modulate BM-MSC functional impairments and thus slow down the progression of neuropathy.

已知长期糖尿病下血管生成和神经营养因子的缺乏会导致雪旺氏细胞变性，临床上表现为糖尿病性神经病 (DN)。虽然外源同种异体间充质基质细胞 (MSC) 的移植已显示通过旁分泌作用改善 DN，但尚不清楚慢性糖尿病下内源性骨髓 MSC 在归巢、迁移和/或旁分泌信号传导方面发生了什么功能变化。参考糖尿病神经病变的终点临床表现。因此，我们旨在确定 1 型糖尿病下 BM-MSC 在存活、自我更新、氧化状态、旁分泌活性、细胞内 Ca ^{2+ 方面的变化}响应病理细胞因子/趋化因子的反应和迁移，参考大鼠模型中神经传导速度 (NCV) 下降的时间点。在糖尿病诱导的 1 周内，BM-MSCs 发生凋亡，并损害其自我更新能力、抗氧化防御机制和向细胞因子/趋化因子的迁移；而仅在三周后观察到神经外膜血管增厚和脱髓鞘导致 NCV 下降。糖尿病诱导后2-3周，BM-MSC凋亡减少，增殖能力恢复；然而，它们的自我更新、迁移和细胞内 Ca ²⁺对病理细胞因子/趋化因子的反应仍然受损。这些结果表明 T1D 诱导的内源性 BM-MSCs 的内在功能障碍发生在神经病变发作之前。BM-MSC 功能改变的时间线也表明，早期针对骨髓生态位的治疗策略可能有助于调节 BM-MSC 功能障碍，从而减缓神经病变的进展。