MSCs ameliorates DPN induced cellular pathology via [Ca²⁺]_i homeostasis and scavenging the pro‐inflammatory cytokines

Abstract

The MSCs of various origins are known to ameliorate or modulate cell survival strategies. We investigated, whether UCB MSCs could improve the survival of the human neuronal cells and/or fibroblast assaulted with DPN sera. The results showed, the co-culture of UCB MSCs with human neuronal cells and/or fibroblasts could effectively scavenge the pro-inflammatory cytokines TNF-α, IL-1β, IFN-ɤ and IL - 12 and control the pro-apoptotic expression of p53/Bax. Further co-culture of UCB MSCs have shown to induce anti-inflammatory cytokines like IL-4, IL-10 and TGF-β and anti-apoptotic Bclxl/Bcl2 expression in the DPN sera stressed cells. Amelioration of elevated [Ca ] and cROS, the portent behind the NFκB/Caspase-3 mediated inflammation in DPN rescued the cells from apoptosis. The results of systemic administration of BM MSCs improved DPN pathology in rat as extrapolated from human cell model. The BM MSCs ameliorated prolonged distal motor latency (control: 0.70 ± 0.06, DPN: 1.29 ± 0.13 m/s DPN + BM MSCs: 0.89 ± 0.02 m/s, p < 0.05) and lowered high amplitude of compound muscle action potentials (CMAPs) (control: 12.36 ± 0.41, DPN: 7.52 ± 0.61 mV, DPN + MSCs: 8.79 ± 0.53 mV, p < 0.05), while slowly restoring the plasma glucose levels. Together, all these results showed that administration of BM or UCB MSCs improved the DPN via ameliorating pro-inflammatory cytokine signaling and [Ca ] homeostasis.

Mesenchymal Stem Cells (MSCs) Coculture Protects [Ca2+]i Orchestrated Oxidant Mediated Damage in Differentiated Neurons In Vitro

“…Excessive ROS are further attributed to increased [Ca 2+ ] i levels released by the calcium store (endoplasmic reticulum (ER)) during inflammation [42]. Our previous publications on cellular and bioenergetics models [21,43,44] have shown the increase in basal [Ca 2+ ] i that, in turn, increases ROS production, as observed in our results. This may be due to mitochondrial Ca 2+ buffering action, which, in turn, resulted in ΔΨ m depolarization, promoting ROS production and subsequent apoptosis [43].…”

“…Post confluence, UCB MSCs were enriched for CD73, CD29, and CD105 using positive selection magnetic-cell sorting, and purity was enumerated by acquiring in Beckman Coulter Novus flow cytometer (Indianapolis, IN, USA). The purity is determined by presence MSCs which are positive for CD105 and CD90 expression, and negative for CD34 and CD45 [21].…”

Involvement of microRNA-146a in diabetic peripheral neuropathy through the regulation of inflammation

“…Molecular studies have revealed that abnormal expression of inflammatory cytokines in the microvasculature around peripheral nerves is found in DPN patients and relevant animal models. 7 , 8 The precise process by which inflammatory damage to peripheral nerves occurs requires further clarification.…”

Cortex Mori Radicis extract promotes neurite outgrowth in diabetic rats by activating PI3K/AKT signaling and inhibiting Ca2+ influx associated with the upregulation of transient receptor potential canonical channel 1

“…Diabetic neuropathy potentiated the activity of T-type and high voltage-activated Ca 2+ channels in primary sensory neurons (30). A recent study showed that mesenchymal stem cells improved DPN by ameliorating intracellular Ca 2+ homeostasis (31). Ca 2+ signaling-associated factors in DRG neurons include several types of Ca 2+ -permeable membrane channels (32).…”