Physiological Cell Reprogramming At The Site Of Tissue Injury Critical Role Of Mir-21
Mithun Sinha1, Kanhaiya Singh1, Amitava Das1, Subhadip Ghatak1, Heather Powell2, Brian Rhea1, Britani Blackstone2, Savita Khanna1, Chandan K Sen1, Sashwati Roy1.
1Comprehensive Wound Center, Center for Regenerative Medicine and Cell Based Therapies, The Ohio State University, Columbus, OH, USA, 2Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.
Background-Wound healing is a complex and dynamic process of repairing and restoring injured tissues. We propose that the wound mileu acts as a cradle for physiological cell reprogramming. Such reprogramming plays a critical role in tissue repair. MicroRNAs (miRs) are small non-coding RNAs that enact post-transcriptional gene silencing. miRs determine the pattern of the injury-inducible transcriptome and therefore healing outcomes. In 2009, our laboratory reported a critical role of miR-21 in myocardial injury, cited>600x. Methods- A tamoxifen inducible K14CremiR-21Δ/Δ mice model was developed resulting in targeted knock down of miR-21 is epithelial of skin. Results-Resolution of inflammatory phase was delayed in wounds of K-14Cre-miR-21-/- mice. Immuno-histochemical staining revealed abundance of macrophages at day 10 post-wounding (p<0.05). Cytokine analyses from the wound fluid of these transgenic mice revealed increased abundance of inflammatory cytokines regulated by miR-21. K14CremiR-21Δ/Δ mice showed compromised quality of healed wounds as demonstrated by reduced collagen (Masson’s trichrome staining; p<0.05). Transition of one cell type to the other is emerging to be a very vital process in tissue remodeling. We observed transition of macrophages to fibroblast-like cells at the site of injury and found that this transition was blunted in K14CremiR-21Δ/Δ mice. Through in vitro and in vivo experiments, we found that miR-21 played a crucial role in shifting the equilibrium towards conversion of macrophages to fibroblast-like cells. miR-21 levels are reduced in pathological conditions, such as diabetes which compromises conversion of macrophages to fibroblast-like cells, thus resulting in impaired wound healing. Conclusion-Conversion of one cell type to another is a part of the normal physiologic process, abundant during tissue repair. This work demonstrates a critical role of miR-21 in such conversion of macrophages to fibroblast-like cells at the wound site.
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