Department of Biophysics, National Institute of Mental Health and Neurosciences, Bengaluru 560029, Karnataka, India.
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru 560029, Karnataka, India.
Biochim Biophys Acta Mol Basis Dis. 2021 Oct 1;1867(10):166187. doi: 10.1016/j.bbadis.2021.166187. Epub 2021 Jun 5.
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 Ca 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 Ca 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.
已知长期糖尿病会导致血管生成和神经营养因子缺乏，从而导致施万细胞退化，临床上表现为糖尿病神经病变（DN）。虽然外源性同种异体间充质基质细胞（MSCs）的移植已通过旁分泌作用显示出对 DN 的改善作用，但尚不清楚慢性糖尿病条件下内源性骨髓间充质基质细胞在归巢、迁移和/或旁分泌信号方面会发生哪些功能变化，以参照糖尿病神经病变的终点临床症状。因此，我们旨在确定 1 型糖尿病条件下 BM-MSCs 在外周血干细胞移植中的变化，以确定其在生存率、自我更新、氧化状态、旁分泌活性、细胞内 Ca 反应和迁移方面的变化，以参照神经传导速度（NCV）下降的时间点在大鼠模型中。在糖尿病诱导后一周内，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/趋化因子的迁移能力；而神经外膜血管增厚和脱髓鞘导致 NCV 下降仅在 3 周后才观察到。在糖尿病诱导后 2 至 3 周，BM-MSC 凋亡减少，增殖能力得到恢复；然而，它们的自我更新、迁移和对病理细胞因子/趋化因子的细胞内 Ca 反应仍然受损。这些结果表明，T1D 诱导的内源性 BM-MSCs 固有功能障碍发生在神经病发生之前。BM-MSCs 功能改变的这一时间线也表明，早期针对骨髓龛的治疗策略可能有助于调节 BM-MSC 的功能障碍，从而减缓神经病的进展。
