ABCB5+ Dermal Stem Cells In Regenerative Wound Healing

描述（由申请人提供）： 慢性皮肤伤口对退伍军人造成严重的健康问题，包括战时持续性创伤、脊髓损伤、糖尿病和血管功能不全。创伤愈合是一个高度调节的过程，涉及细胞迁移、增殖和细胞外基质蛋白的分泌。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过度愈合（瘢痕疙瘩形成）或愈合不充分。干细胞移植在再生医学领域具有很大的前景，并已在一些临床前模型中显示出有助于再生伤口愈合。然而，目前无法获得分子定义的纯干细胞群体，其具有所采用的分离标记物的已建立的功能相关性，以及可用的干细胞群体再生正常皮肤附件的有限能力，代表了更广泛的治疗益处和基于干细胞的治疗策略最终成功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再生伤口愈合方法来解决这些障碍，该方法采用了新发现的具有多能体外和体内分化可塑性的真皮干细胞群，其定义为ATP结合盒转运蛋白ABCB 5的表达。基于我们对这种新型干细胞群体的多能分化可塑性的发现，通过我们在新创建的ABCB 5敲除小鼠中证实ABCB 5在干细胞自我更新、正常皮肤发育和伤口愈合中的功能作用而得到加强，我们假设人ABCB 5+真皮干细胞移植将显著改善与免疫相关的同基因人源化移植模型中的再生伤口愈合。因此，预计这一举措将为最终成功应用新型个性化干细胞治疗方式为退伍军人遭受皮肤伤口，发病率和死亡率的主要来源铺平道路。

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.