Abstract
Human mesenchymal/stromal stem cells (hMSC) are the most promising cell source for adult cell therapies in regenerative medicine. Many clinical trials have reported the use of autologous transplantation of hMSCs in several disorders, but with limited results. To exert their potential, hMSCs could exhibit efficient homing and migration toward lesion sites among other effects, but the underlying process is not clear enough. To further increase the knowledge, we studied the co-regulation between hypoxia-regulated genes and miRNAs. To this end, we investigated the miRNA expression profile of healthy hMSCs in low oxygen/nutrient conditions to mimic ischemia and compared with cells of patients suffering from critical limb ischemia (CLI). miRNAs are small, highly conserved, non-coding RNAs, skilled in the control of the target’s expression level in a fine-tuned way. After analyzing the miRNOme in CLI-derived hMSC cells and healthy controls, and intersecting the results with the mRNA expression dataset under hypoxic conditions, we identified two miRNAs potentially relevant to the disease: miR-29b as a pathological marker of the disease and miR-638 as a therapeutic target. This study yielded a deeper understanding of stem cell biology and ischemic disorders, opening new potential treatments in the future.
Highlights
Ischemic disorders are characterized by reduced blood flow to a tissue or organ due to unfavorable vascular conditions, generally caused by atherosclerosis, such as stroke, myocardial infarction, and critical limb ischemia (CLI)
We investigated the miRNA expression profile of healthy Human mesenchymal/stromal stem cells (hMSC) in low oxygen/nutrient conditions to mimic ischemia and compared with cells of patients suffering from critical limb ischemia (CLI). miRNAs are small, highly conserved, non-coding RNAs, skilled in the control of the target’s expression level in a fine-tuned way
On deeper analysis of the miRNA expression profiles, we identified a cluster of 15 common miRNAs modified in healthy hMSCs exposed to pathological conditions (0.5% O2 + 0.5% fetal bovine serum (FBS)) and in
Summary
Ischemic disorders are characterized by reduced blood flow to a tissue or organ due to unfavorable vascular conditions, generally caused by atherosclerosis, such as stroke, myocardial infarction, and critical limb ischemia (CLI). The benefits observed in preclinical animal model studies have not been convincingly reproduced in ongoing clinical trials due to poor cell engraftment, short cell persistence after transplantation, and low cell survival rate [7] This may be due in part to the lack of suitable human ischemic models for unequivocally assessing the cell dosage, cell source, and administration methods of hMSCs to promote blood flow regeneration and the functional recovery of affected tissues or organs to avoid fatal consequences. A gene therapy approach has been explored, in which genetic material encoding for proteins that may help to increase revascularization is injected into patients, but it showed no clear differences between treatment groups [8] The failure of these procedures may suggest that either MSC therapeutic mechanisms remain elusive or that the disease condition affects the results. This study is the first to identify the co-regulatory network among the hypoxia-regulated genes and miRNAs in human mesenchymal stem cells (hMSCs), the most promising cell source for cell therapies in regenerative medicine
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