Chronic cutaneous wounds pose significant health problems for Veterans with diverse medical conditions, including wartime-sustained trauma, spinal cord injury, diabetes and vascular insufficiency. Wound healing is a highly regulated process involving cell migration, proliferation and secretion of extracellular matrix proteins. Dysregulation of these cellular and molecular signaling cascades may result in either excessive healing (keloid scar formation) or inadequate healing in patients with diabetes, vascular insufficiency, or burns. Stem cell transplantation carries great promise in the field of regenerative medicine and has been shown to contribute to regenerative wound healing in some pre-clinical models. However, the current unavailability of molecularly-defined, pure stem cell populations with established functional relevance of employed isolation markers, and the limited capacity of available stem cell populations to regenerate normal skin appendages, represent significant barriers to broader therapeutic benefit and eventual successful translation of stem cell-based treatment strategies to the clinic. This study aims to address these obstacles by establishing a novel stem cell-based approach to regenerative wound healing that employs a newly discovered dermal stem cell population with multipotent in vitro and in vivo differentiation plasticity, defined by expression of the ATP-bindig cassette transporter, ABCB5. Based on our findings of multipotent differentiation plasticity of thi novel stem cell population, fortified by our demonstration of functional roles of ABCB5 in stem cell self-renewal, normal skin development and wound healing in newly created ABCB5 knockout mice, we hypothesize that human ABCB5+ dermal stem cell grafting will significantly improve regenerative wound healing in translationally relevant syngeneic humanized transplantation models. As a result, this initiative is anticipated to pave the way towards eventual successful application of novel personalized stem cell-based treatment modalities for Veterans afflicted by cutaneous wounds, a major source of morbidity and mortality.

Public Health Relevance

Chronic cutaneous wounds pose significant health problems for Veterans with diverse medical conditions such as wartime-sustained trauma, spinal cord injury, diabetes and vascular insufficiency. During recent conflicts in Iraq and Afganistan, many troops experienced severe traumatic injuries, e.g. spinal cord injury and massive burns. Many of these veterans are at risk of developing chronic wounds as a consequence of immobility and pressure ulcers. The current study aims to establish novel personalized stem cell-based therapeutic approaches to regenerative wound healing using stem cells isolated from human skin. Specifically, we will identify a new source of purified multipotent stem cells for transplantation, which will have the potential to substantially increase the success of wound healing in Veterans.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX000989-02
Application #
8990405
Study Section
Spinal Cord Injury & Regenerative Medicine (RRD0)
Project Start
2013-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
VA Boston Health Care System
Department
Type
DUNS #
034432265
City
Boston
State
MA
Country
United States
Zip Code
02130
Gonzalez, Gabriel; Sasamoto, Yuzuru; Ksander, Bruce R et al. (2018) Limbal stem cells: identity, developmental origin, and therapeutic potential. Wiley Interdiscip Rev Dev Biol 7:
Guo, Qin; Grimmig, Tanja; Gonzalez, Gabriel et al. (2018) ATP-binding cassette member B5 (ABCB5) promotes tumor cell invasiveness in human colorectal cancer. J Biol Chem 293:11166-11178
Sasamoto, Yuzuru; Ksander, Bruce R; Frank, Markus H et al. (2018) Repairing the corneal epithelium using limbal stem cells or alternative cell-based therapies. Expert Opin Biol Ther 18:505-513
Webber, Beau R; O'Connor, Kyle T; McElmurry, Ron T et al. (2017) Rapid generation of Col7a1-/- mouse model of recessive dystrophic epidermolysis bullosa and partial rescue via immunosuppressive dermal mesenchymal stem cells. Lab Invest 97:1218-1224
Jiang, Dongsheng; Muschhammer, Jana; Qi, Yu et al. (2016) Suppression of Neutrophil-Mediated Tissue Damage-A Novel Skill of Mesenchymal Stem Cells. Stem Cells 34:2393-406
Frank, Markus H; Frank, Natasha Y (2015) Restoring the cornea from limbal stem cells. Regen Med 10:1-4
Sheu, J; Divito, S J; Hoffman, E P et al. (2015) Mosaic focal dermal hypoplasia caused by a novel somatic mutation in PORCN detected in affected skin. Br J Dermatol 173:568-70
de Waard, Nadine E; Kolovou, Paraskevi E; McGuire, Sean P et al. (2015) Expression of Multidrug Resistance Transporter ABCB5 in a Murine Model of Human Conjunctival Melanoma. Ocul Oncol Pathol 1:182-189
Schatton, Tobias; Yang, Jun; Kleffel, Sonja et al. (2015) ABCB5 Identifies Immunoregulatory Dermal Cells. Cell Rep 12:1564-74
Volpicelli, Elgida R; Lezcano, Cecilia; Zhan, Qian et al. (2014) The multidrug-resistance transporter ABCB5 is expressed in human placenta. Int J Gynecol Pathol 33:45-51

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