Modulating the extracellular matrix to treat wound healing defects in Ehlers-Danlos syndrome
Kindra M. Kelly-Scumpia,
Maani M. Archang,
Prabhat K. Purbey,
Tomohiro Yokota,
Rimao Wu,
Jackie McCourt,
Shen Li,
Rachelle H. Crosbie,
Philip O. Scumpia,
Arjun Deb
Affiliations
Kindra M. Kelly-Scumpia
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
Maani M. Archang
Bioengineering Department, University of California, Los Angeles, Los Angeles, CA, USA; Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Dermatology, VA Greater Los Angeles Healthcare System-West Los Angeles, Los Angeles, CA 90073, USA
Prabhat K. Purbey
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Tomohiro Yokota
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
Rimao Wu
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jackie McCourt
Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Shen Li
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
Rachelle H. Crosbie
Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
Philip O. Scumpia
Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Dermatology, VA Greater Los Angeles Healthcare System-West Los Angeles, Los Angeles, CA 90073, USA
Arjun Deb
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author
Summary: Classic Ehlers-Danlos syndrome (cEDS) is a genetic disorder of the connective tissue that is characterized by mutations in genes coding type V collagen. Wound healing defects are characteristic of cEDS and no therapeutic strategies exist. Herein we describe a murine model of cEDS that phenocopies wound healing defects seen in humans. Our model features mice with conditional loss of Col5a1 in Col1a2+ fibroblasts (Col5a1CKO). This model shows that an abnormal extracellular matrix (ECM) characterized by fibrillar disarray, altered mechanical properties, and decreased collagen deposition contribute to the wound healing defect. The cEDS animals exhibit decreased expression of epidermal genes and increased inflammation. Finally, we demonstrate that inhibiting mechanosensitive integrin signaling or by injecting wild-type (WT) fibroblasts into cEDS animals enhances epidermal gene expression, decreases inflammation, and augments wound closure. These findings suggest that cell delivery and/or blocking integrin signaling are potentially therapeutic strategies to rescue wound healing defects in cEDS.
