Intravenously Injected Human Fibroblasts Home to Skin Wounds, Deliver Type VII Collagen, and Promote Wound Healing

Woodley, David T.; Remington, Jennifer; Huang, Yi; Hou, Yingping; Li, Wei; Keene, Douglas R.; Chen, Mei

doi:10.1038/sj.mt.6300041

Cited by 95 publications

(71 citation statements)

References 33 publications

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“…Woodley et al (28) recently reported that i.v. injection of human fibroblasts induces systemic production of human collagen VII in immunodeficient mice; however, major ethical and safety problems remain in human patients.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice

Fujita

Abe

Inokuma

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Attempts to treat congenital protein deficiencies using bone marrow-derived cells have been reported. These efforts have been based on the concepts of stem cell plasticity. However, it is considered more difficult to restore structural proteins than to restore secretory enzymes. This study aims to clarify whether bone marrow transplantation (BMT) treatment can rescue epidermolysis bullosa (EB) caused by defects in keratinocyte structural proteins. BMT treatment of adult collagen XVII (Col17) knockout mice induced donor-derived keratinocytes and Col17 expression associated with the recovery of hemidesmosomal structure and better skin manifestations, as well improving the survival rate. Both hematopoietic and mesenchymal stem cells have the potential to produce Col17 in the BMT treatment model. Furthermore, human cord blood CD34 + cells also differentiated into keratinocytes and expressed human skin component proteins in transplanted immunocompromised (NOD/SCID/γ c null ) mice. The current conventional BMT techniques have significant potential as a systemic therapeutic approach for the treatment of human EB.

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Section: Discussionmentioning

confidence: 99%

Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice

Fujita

Abe

Inokuma

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…However, direct evidence that purified C7 alone promotes keratinocyte motility was lacking. Our recent studies showed that there was a dramatic enhancement of skin wound closure in both murine and human skin wounds when wild type C7 was delivered early to healing wounds (37). These data suggest that C7 may possess properties that enhance cell migration.…”

Section: Resultsmentioning

confidence: 91%

“…In previous studies we observed that the wounds of mice IV injected with gene-corrected RDEB fibroblasts overexpressing C7 demonstrated accelerated wound healing compared with control mice injected with uncorrected RDEB cells (37). Similarly, C7 delivered to the wound bed via intradermal or intravenous injection of the recombinant protein also promoted accelerated closure of skin wounds.…”

Section: Figure 9 Migration Of Human Keratinocytes On Various C7 Mutmentioning

confidence: 98%

Characterization of Molecular Mechanisms Underlying Mutations in Dystrophic Epidermolysis Bullosa Using Site-directed Mutagenesis

Woodley

Hou

Martín

et al. 2008

Journal of Biological Chemistry

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Type VII collagen (C7) is a major component of anchoring fibrils, structures that mediate epidermal-dermal adherence. Mutations in gene COL7A1 encoding for C7 cause dystrophic epidermolysis bullosa (DEB), a genetic mechano-bullous disease. The biological consequences of specific COL7A1 mutations and the molecular mechanisms leading to DEB clinical phenotypes are unknown. In an attempt to establish genotype-phenotype relationships, we generated four individual substitution mutations that have been associated with recessive DEB, G2049E, R2063W, G2569R, and G2575R, and purified the recombinant mutant proteins. All mutant proteins were synthesized and secreted as a 290-kDa mutant C7 ␣ chain at levels similar to wild type C7. The G2569R and G2575R glycine substitution mutations resulted in mutant C7 with increased sensitivity to protease degradation and decreased ability to form trimers. Limited proteolytic digestion of mutant G2049E and R2063W proteins yielded aberrant fragments and a triple helix with reduced stability. These two mutations next to the 39-amino acid helical interruption hinge region caused local destabilization of the triple-helix that exposed an additional highly sensitive proteolytic site within the region of the mutation. Our functional studies demonstrated that C7 is a potent pro-motility matrix for skin human keratinocyte migration and that this activity resides within the triple helical domain. Furthermore, G2049E and R2063W mutations reduced the ability of C7 to support fibroblast adhesion and keratinocyte migration. We conclude that known recessive DEB C7 mutations perturb critical functions of the C7 molecule and likely contribute to the clinical phenotypes of DEB patients.Type VII collagen (C7) 3 resides within the basement membrane zone beneath stratified squamous epithelium (1, 2). C7 is a major component of anchoring fibrils, structures that attach the epidermal basement membrane of the skin to the underlying papillary dermis (3, 4). In hereditary dystrophic epidermolysis bullosa (DEB), anchoring fibrils are diminutive and/or reduced in number (5-7). DEB is caused by mutations in the COL7A1 gene encoding C7 (8 -11).C7 is a homotrimer composed of three identical ␣ chains. Each ␣ chain has a 145-kDa central collagenous triple-helical segment characterized by repeating Gly-X-Y amino acid sequences. The helical central domain is flanked by a large 145-kDa amino-terminal, noncollagenous domain (NC1) and a small 34-kDa carboxyl-terminal non-collagenous domain (NC2) (4, 12). Within the papillary dermis, C7 molecules form antiparallel, tail-to-tail dimers stabilized by disulfide bonding through a small carboxyl-terminal NC2 overlap between two C7 molecules. A portion of the NC2 domain is then proteolytically removed (13,14). The antiparallel dimers then aggregate laterally to form anchoring fibrils which interact with microfibrils, collagen fibrils, and micro-thread-like fibers within the papillary dermis. These interactions are thought to secure the epidermis and its underlying basement membra...

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“…A feared complication of RDEB is squamous cell carcinoma, which arises at an early age in trauma-prone skin areas (15,16). Although clinical observations suggest that wound closure is impaired in RDEB (19)(20)(21), no study thus far has addressed the role of COL7A1 in wound healing.…”

Section: Introductionmentioning

confidence: 99%

Collagen VII plays a dual role in wound healing

Nyström¹,

Velati²,

Mittapalli³

et al. 2013

J. Clin. Invest.

181

168

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Although a host of intracellular signals is known to contribute to wound healing, the role of the cell microenvironment in tissue repair remains elusive. Here we employed 2 different mouse models of genetic skin fragility to assess the role of the basement membrane protein collagen VII (COL7A1) in wound healing. COL7A1 secures the attachment of the epidermis to the dermis, and its mutations cause a human skin fragility disorder coined recessive dystrophic epidermolysis bullosa (RDEB) that is associated with a constant wound burden. We show that COL7A1 is instrumental for skin wound closure by 2 interconnected mechanisms. First, COL7A1 was required for re-epithelialization through organization of laminin-332 at the dermal-epidermal junction. Its loss perturbs laminin-332 organization during wound healing, which in turn abrogates strictly polarized expression of integrin α6β4 in basal keratinocytes and negatively impacts the laminin-332/integrin α6β4 signaling axis guiding keratinocyte migration. Second, COL7A1 supported dermal fibroblast migration and regulates their cytokine production in the granulation tissue. These findings, which were validated in human wounds, identify COL7A1 as a critical player in physiological wound healing in humans and mice and may facilitate development of therapeutic strategies not only for RDEB, but also for other chronic wounds.

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Intravenously Injected Human Fibroblasts Home to Skin Wounds, Deliver Type VII Collagen, and Promote Wound Healing

Cited by 95 publications

References 33 publications

Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice

Bone marrow transplantation restores epidermal basement membrane protein expression and rescues epidermolysis bullosa model mice

Characterization of Molecular Mechanisms Underlying Mutations in Dystrophic Epidermolysis Bullosa Using Site-directed Mutagenesis

Collagen VII plays a dual role in wound healing

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