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Distant mesenchymal progenitors contribute to skin wound healing and produce collagen: evidence from a murine fetal microchimerism model.

ABSTRACT: The contribution of distant and/or bone marrow-derived endogenous mesenchymal stem cells (MSC) to skin wounds is controversial. Bone marrow transplantation experiments employed to address this have been largely confounded by radiation-resistant host-derived MSC populations. Gestationally-acquired fetal MSC are known to engraft in maternal bone marrow in all pregnancies and persist for decades. These fetal cells home to damaged maternal tissues, mirroring endogenous stem cell behavior. We used fetal microchimerism as a tool to investigate the natural homing and engraftment of distant MSC to skin wounds. Post-partum wild-type mothers that had delivered transgenic pups expressing luciferase under the collagen type I-promoter were wounded. In vivo bioluminescence imaging (BLI) was then used to track recruitment of fetal cells expressing this mesenchymal marker over 14 days of healing. Fetal cells were detected in 9/43 animals using BLI (Fisher exact p = 0.01 versus 1/43 controls). These collagen type I-expressing fetal cells were specifically recruited to maternal wounds in the initial phases of healing, peaking on day 1 (n = 43, p<0.01). This was confirmed by detection of Y-chromosome+ve fetal cells that displayed fibroblast-like morphology. Histological analyses of day 7 wounds revealed vimentin-expressing fetal cells in dermal tissue. Our results demonstrate the participation of distant mesenchymal cells in skin wounds. These data imply that endogenous MSC populations are likely recruited from bone marrow to wounds to participate in healing.

SUBMITTER: Seppanen E

PROVIDER: S-EPMC3641113 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Distant mesenchymal progenitors contribute to skin wound healing and produce collagen: evidence from a murine fetal microchimerism model.

Seppanen Elke E Roy Edwige E Ellis Rebecca R Bou-Gharios George G Fisk Nicholas M NM Khosrotehrani Kiarash K

PloS one 20130501 5

The contribution of distant and/or bone marrow-derived endogenous mesenchymal stem cells (MSC) to skin wounds is controversial. Bone marrow transplantation experiments employed to address this have been largely confounded by radiation-resistant host-derived MSC populations. Gestationally-acquired fetal MSC are known to engraft in maternal bone marrow in all pregnancies and persist for decades. These fetal cells home to damaged maternal tissues, mirroring endogenous stem cell behavior. We used fe ...[more]

PMID: 23650524

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Project description:Porous collagen-glycosaminoglycan (collagen-GAG) scaffolds have shown promising clinical results for wound healing; however, these scaffolds do not replace the dermal and epidermal layer simultaneously and rely on local endogenous signaling to direct healing. Functionalizing collagen-GAG scaffolds with signaling factors, and/or additional matrix molecules, could help overcome these challenges. An ideal candidate for this is platelet-rich plasma (PRP) as it is a natural reservoir of growth factors, can be activated to form a fibrin gel, and is available intraoperatively. We tested the factors released from PRP (PRPr) and found that at specific concentrations, PRPr enhanced cell proliferation and migration and induced angiogenesis to a greater extent than fetal bovine serum (FBS) controls. This motivated us to develop a strategy to successfully incorporate PRP homogeneously within the pores of the collagen-GAG scaffolds. The composite scaffold released key growth factors for wound healing (FGF, TGFβ) and vascularization (VEGF, PDGF) for up to 14 days. In addition, the composite scaffold had enhanced mechanical properties (when compared to PRP gel alone), while providing a continuous upper surface of extracellular matrix (ECM) for keratinocyte seeding. The levels of the factors released from the composite scaffold were sufficient to sustain proliferation of key cells involved in wound healing, including human endothelial cells, mesenchymal stromal cells, fibroblasts, and keratinocytes; even in the absence of FBS supplementation. In functional in vitro and in vivo vascularization assays, our composite scaffold demonstrated increased angiogenic and vascularization potential, which is known to lead to enhanced wound healing. Upon pro-inflammatory induction, macrophages released lower levels of the pro-inflammatory marker MIP-1α when treated with PRPr; and released higher levels of the anti-inflammatory marker IL1-ra upon both pro- and anti-inflammatory induction when treated with the composite scaffold. Finally, our composite scaffold supported a co-culture system of human fibroblasts and keratinocytes that resulted in an epidermal-like layer, with keratinocytes constrained to the surface of the scaffold; by contrast, keratinocytes were observed infiltrating the PRP-free scaffold. This novel composite scaffold has the potential for rapid translation to the clinic by isolating PRP from a patient intraoperatively and combining it with regulatory approved scaffolds to enhance wound repair.

Dataset Information

Distant mesenchymal progenitors contribute to skin wound healing and produce collagen: evidence from a murine fetal microchimerism model.

Publications

Distant mesenchymal progenitors contribute to skin wound healing and produce collagen: evidence from a murine fetal microchimerism model.

Similar Datasets

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