Autologous micrograft accelerates endogenous wound healing response through ERK-induced cell migration

Abstract

Defective fibroblast migration causes delayed wound healing (WH) and chronic skin lesions. Autologous micrograft (AMG) therapies have recently emerged as a new effective treatment able to improve wound healing capacity. However, the molecular mechanisms connecting their beneficial outcomes with the wound healing process are still unrevealed. Here, we show that AMG modulates primary fibroblast migration and accelerates skin re-epithelialization without affecting cell proliferation. We demonstrate that AMG is enriched in a pool of WH-associated growth factors that may provide the initiation signal for a faster endogenous wound healing response. This, in turn leads to increased cell migration rate by elevating activity of extracellular signal-regulated kinase (ERK) pathway and subsequent activation of matrix metalloproteinase expression and their extracellular enzymatic activity. Moreover, AMG-treated wounds showed increased granulation tissue formation and organized collagen content. Overall, we shed light on AMG molecular mechanism supporting its potential to trigger a highly improved wound healing process. Funding: This work is supported by the contribution of NATO grant "RAWINTS" project G984961: Rapid Skin Wound Healing by INtegrated Tissue engineering and Sensing. We are grateful for the support from KU Leuven starting grant (STG), KU Leuven C1 funds (C14/16/078) and FWO (G097618N) funds to F.LL; FWO (#G088715N, #G060612N, #G0A8813N). CARIPLO Foundation #2015, C1 funds (C14/17/111) and Opening the future #EJJ-C4851-17/07-P to M.S.

Acceleration of Skin Wound-Healing Reactions by Autologous Micrograft Tissue Suspension

“…Therefore, a comprehensive reaction during the progress of wound-healing occurs. This becomes clear in molecular mechanisms of repair in acute and chronic wounds [ 22 ]. However, applying this knowledge to intractable human wounds is still not sufficient, because complex cellular interactions take place during the wound-healing process.…”

“…Thus, it is reasonable to conclude that CEL and REL showed a significant correlation ( Figure 4 B). Recently, Balli et al [ 22 ] showed that the MG tissue solution without cells activated the extracellular signal-regulated kinase to induce gene transductions of matrix metalloproteinases and cell migration in vitro. More recently, they found that the mechanism involved phosphorylation of c-Jun and Fos-related antigen-1 [ 37 ].…”

PCSK9-D374Y Suppresses Hepatocyte Migration through Downregulating Free Cholesterol Efflux Rate and Activity of Extracellular Signal-Regulated Kinase

“…The activity of ERK signaling pathway has been proved to be involved in the regulation of cell migration in previous works. For example, in wound healing experiments, the migration of keratinocytes was enhanced by micrograft treatment through ERK activation [32]. Another research indicated that ovarian cancer cell migration was induced by betacellulin through EGFR-MEK/ERK signaling [33].…”

Effects of autologous micrografts on stable bilateral vitiligo: A focus on hand lesions

“…The Rigenera disaggregation process allows the collection of any component of the tissue tissue, 24 hair roots included, which are known to contain a pool of undifferentiated melanocyte progenitors cells; 25 we can thus speculate that the mechanism responsible for the repigmentation is due to the grafting of the melanocytes collected by the hair follicles, and secondarily, because in vitro characterization of the micrografts showed that those are enriched in progenitor cells expressing mesenchymal stem cell-like markers such as CD90, CD73 and CD105, but also growth factors and extracellular matrix, 23,26 accounting for the immunomodulatory and regenerative outcome. 27 To summarize, this specific micrografts technology has different advantages: (i) the use of autologous sample which are almost immediately (2 min) disaggregated/used; and (ii) differing from other protocols described in the published work, the amount of sample collected is extremely smaller (1:10 vs 1:200 ratio).…”