Bone marrow-derived fibroblasts in skin wound healing. Nearly 25% of all diabetic patients, with foot ulcers, will inevitably progress to major limb amputation. Diabetic wound healing deficiencies are associated with impaired tissue level neovascularization, impaired keratinocyte function, reduced tensile strength, and higher infection rates. While these generalized poor wound healing defects of patients with diabetes mellitus are well established, the specific tissue level mechanisms responsible for these wound-healing deficiencies remain poorly understood. A complex cellular cascade mediates normal cutaneous wound healing, where all skin cells cooperate to repair and rebuild the dermis and epidermis. But in patients with chronic wounds, these signals for cell recruitment, proliferation, and differentiation in the wound bed are disrupted. Overall, we aim to develop new strategies for treating chronic leg wounds by primarily identifying specific molecules, that when expressed by cells within the wound itself, will promote healing of chronic wounds as well as fully restore skin architecture and function. Because fibroblasts are the critical cell type for early and late wound healing, we hypothesize that, during normal wound healing, fibroblast precursor cells are recruited from both, the resident resting pool in the skin and the bone marrow-derived stem cell populations, which then subsequently migrate into the wound bed and differentiateinto mature fibroblasts. To distinguish between these two cellular populations we have developed in vivo bone marrow transplantation models, using normal and diabetic mice, and novel in vitro three-dimensional reconstructions of human dermis, vascularized dermis, and skin, in which fibroblasts can interact with other key cell types involved in wound healing. In these in vivo wound-healing models and in vitro reconstructionswe will determine the extent to which bone marrow-derived fibroblasts influence wound- healing processes including contraction of collagen, stimulation of vessel formation, re-epithelialization and keratinocyte growth and differentiation. With the use of viral vector delivery of agonists and inhibitors, we will test the hypothesis that growth factors, specifically PDGF-B (platelet-derived growth factor) are critical for the activation of bone marrow-derived fibroblasts to invade into collagen, proliferate, migrate to the wound, survive, and differentiate into long-term cellular components of the healed skin wound.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK071084-06S1
Application #
8034974
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Jones, Teresa L Z
Project Start
2010-03-23
Project End
2011-02-28
Budget Start
2010-03-23
Budget End
2011-02-28
Support Year
6
Fiscal Year
2010
Total Cost
$129,787
Indirect Cost
Name
University of Miami School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Zhuge, Ying; Regueiro, Manuela M; Tian, Runxia et al. (2018) The effect of estrogen on diabetic wound healing is mediated through increasing the function of various bone marrow-derived progenitor cells. J Vasc Surg 68:127S-135S
Liu, Zhao-Jun; Tian, Runxia; Li, Yan et al. (2016) SDF-1?-induced dual pairs of E-selectin/ligand mediate endothelial progenitor cell homing to critical ischemia. Sci Rep 6:34416
Liu, Zhao-Jun; Daftarian, Pirouz; Kovalski, Letícia et al. (2016) Directing and Potentiating Stem Cell-Mediated Angiogenesis and Tissue Repair by Cell Surface E-Selectin Coating. PLoS One 11:e0154053
Liu, Zhao-Jun; Li, Yan; Tan, Yurong et al. (2012) Inhibition of fibroblast growth by Notch1 signaling is mediated by induction of Wnt11-dependent WISP-1. PLoS One 7:e38811
Liu, Zhao-Jun; Tan, Yurong; Beecham, Gary W et al. (2012) Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis. Atherosclerosis 225:296-303
Castilla, Diego M; Liu, Zhao-Jun; Tian, Runxia et al. (2012) A novel autologous cell-based therapy to promote diabetic wound healing. Ann Surg 256:560-72
Liu, Zhao-Jun; Tian, Runxia; Li, Yan et al. (2011) Inhibition of tumor angiogenesis and melanoma growth by targeting vascular E-selectin. Ann Surg 254:450-6; discussion 456-7
Nedeau, April E; Gallagher, Katherine A; Liu, Zhao-Jun et al. (2011) Elevation of hemopexin-like fragment of matrix metalloproteinase-2 tissue levels inhibits ischemic wound healing and angiogenesis. J Vasc Surg 54:1430-8
Liu, Zhao-Jun; Tian, Runxia; An, Weijun et al. (2010) Identification of E-selectin as a novel target for the regulation of postnatal neovascularization: implications for diabetic wound healing. Ann Surg 252:625-34
Nedeau, April E; Bauer, Richard J; Gallagher, Katherine et al. (2008) A CXCL5- and bFGF-dependent effect of PDGF-B-activated fibroblasts in promoting trafficking and differentiation of bone marrow-derived mesenchymal stem cells. Exp Cell Res 314:2176-86

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