Fibroblasts/myofibroblasts that participate in cutaneous wound healing are not derived from circulating progenitor cells

Abstract

Dermal fibroblasts/myofibroblasts involved in the wound healing are thought to originate from the resident fibroblast progenitors. To test the hypothesis of an extra dermal origin of the dermal fibroblasts/myofibroblasts, bone marrow (BM) transplantation and parabiosis experiments were initiated utilizing a collagen promoter green fluorescent protein (GFP) reporter transgene as a visible marker for dermal fibroblasts/myofibroblasts. BM transplantation experiments using BM from Col3.6GFPsapph transgenic mice showed no evidence that BM derived progenitors differentiated into dermal fibroblasts/myofibroblasts at the wound site. Rather the GFP positive cells (GFP+) observed at the wound site were not dermal fibroblasts/myofibroblasts but immune cells. These GFP+ cells were also detected in the lung and spleen. Furthermore, GFP+ fibroblasts were not detected in primary dermal fibroblast cultures initiated from BM chimeras. Using the same transgenic mice, parabiotic pairs were generated. One partner in the parabiosis carried a GFP expressing transgene while the other partner was a non-transgenic C57BL/6 mouse. Similar to the BM transplantation experiments, GFP+ immune cells were detected in the wound of the non-transgenic parabiont, however, GFP expressing dermal fibroblasts/myofibroblasts were not observed. Collectively, these data suggest that dermal fibroblast/myofibroblast progenitors do not readily circulate. The expression of the Col3.6GFPsapph in the hematopoietic cells confirmed that our methods were sensitive enough to detect Col3.6GFP expressing dermal fibroblasts derived from the peripheral circulation if they had originated in the BM.

Fibroblast heterogeneity: implications for human disease

“…This population of fibroblasts have the capacity to differentiate into multiple lineages (23) and have been termed mesenchymal stem or stromal cells (MSCs). Initial reports suggested that MSCs can contribute to the dermis (24)(25)(26), but subsequent studies do not appear to support this finding (27)(28)(29). Interestingly, clinical trials have suggested that the infusion of MSCs into the blood may ameliorate several diseases, such as graft-versus-host disease (30,31).…”

The Effects of (-)-Epigallocatechin-3-Galate on Wound Closure and Infections in Mice

“…35 There is a need to evaluate the efficacy of topical agents that can be used to supplement or enhance current systemic antimicrobial therapies. In the clinical arena, especially following severe trauma, both wound healing and infections are major concerns.…”

“…However, Barisic-Dujmovic et al demonstrated that myofibroblasts within the wound are derived from resident fibroblasts. 35 EGCG has been previously demonstrated to inhibit the differentiation of fibroblasts into myofibroblasts. 26 In vitro, there was a significant reduction in α-SMA staining at the higher doses of EGCG.…”

“…The discrepancy between in vitro and in vivo data suggests that cells are directly exposed to EGCG in culture systems in contrast to in vivo exposures in which tissues are more likely exposed to metabolized products of EGCG rather than intact EGCG. 35 Additionally, the wound is a complex environment and the dose of EGCG that cells see may highly depended on the microenvironment of the wound. As a topical agent, EGCG warrants further investigation into its properties in the context of healing and infection control.…”

Lung Bone Marrow–derived Hematopoietic Progenitor Cells Enhance Pulmonary Fibrosis

“…To date, several lines of evidences suggested that BMDCs, including fibrocytes, expressed collagen (7,18,25,26). Although collagen-expressing BMDCs likely exist, their definition as fibrocytes is not straightforward because of the lack of stable unique markers for this cell type, with many of the markers used being also expressed by any number of different cell types, including macrophages and dendritic cells (8,27).…”