ABCB5+ Dermal Stem Cells In Regenerative Wound Healing

描述(由申请人提供)： 慢性皮肤创伤给退伍军人带来了严重的健康问题，他们的医疗条件多种多样，包括战时持续创伤、脊髓损伤、糖尿病和血管功能不全。创伤愈合是一个高度调控的过程，涉及细胞迁移、增殖和分泌细胞外基质蛋白。这些细胞和分子信号级联的失调可能导致糖尿病、血管功能不全或烧伤患者的过度愈合(瘢痕疙瘩形成)或愈合不足。干细胞移植在再生医学领域有着巨大的前景，在一些临床前模型中已被证明有助于再生伤口的愈合。然而，目前尚无分子定义的、与所用分离标记的功能相关的纯干细胞群体，以及可用干细胞群体再生正常皮肤附件的能力有限，这些都是更广泛的治疗益处和最终成功地将基于干细胞的治疗策略转化为临床的重大障碍。本研究旨在通过建立一种新的基于干细胞的创面再生修复方法来解决这些障碍，该方法使用了新发现的具有体外和体内分化可塑性的真皮干细胞群体，其定义是三磷酸腺苷结合盒转运体ABCB5的表达。基于我们对ABCB5基因敲除小鼠的干细胞自我更新、正常皮肤发育和伤口愈合功能作用的研究结果，我们推测，在翻译相关的同基因人源化移植模型中，人ABCB5+真皮干细胞移植将显著促进再生伤口的愈合。因此，这一倡议预计将为最终成功应用基于干细胞的新型个人化治疗模式铺平道路，以治疗受皮肤创伤困扰的退伍军人，皮肤创伤是发病率和死亡率的主要来源。

DESCRIPTION (provided by applicant): 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.