Multicomponent Therapy for Age-related Skin Stem Cell Deficiency

摘要 慢性溃疡，定义为三个月内不能愈合的伤口，与年龄有关 皮肤干细胞功能障碍不仅有可能阻碍组织修复，还会导致皮肤脆弱， 萎缩和“衰老表型”本身具有临床和心理社会影响。不能愈合 老年人的溃疡在美国和全球社会都是数十亿美元的负担 通过利用卫生保健资源以及通过降低生产率。尽管如此，它仍然是 认识到“基础生物学和与年龄相关的变化对伤口愈合的影响很差” 理解，还有许多研究问题有待回答“。为了解决这一重要问题， 我们已经组建了一支高度协作和多学科的调查团队，拥有既定的轨迹 皮肤病理学、再生和干细胞生物学、伤口愈合、生物信息学和 衰老的病理生物学；2)利用哈佛七所机构的资源，制定了统一的国家-- 最先进的方法来破译皮肤干细胞缺陷在年龄相关的缺陷伤口愈合中的作用； 生成基于数据的假设和确定的项目间协同效应，从而最大限度地提高工作效率和 翻译焦点。我们的基本假设是识别和审问三个主要的、相互关联的 与年龄相关的皮肤干细胞相关的、在治疗上可靶向/可重编程的通路 功能障碍，a)代谢，b)表观遗传，c)膜转运体/受体，将为 组合(多组分)疗法对皮肤更强大的愈合和再生反应是必要的 受伤。我们将通过本组织主要人员制定的六项战略来实现这一目标。 PPG：1)发现用于表皮和真皮干细胞鉴定和操作的生物标志物；2) 测定表皮祖细胞活性和维持所需的代谢调节剂；3)鉴定 控制皮肤干细胞功能和活力的新的表观遗传途径；4)发展和评估 独特的小鼠模型，可以在体内研究人类伤口的愈合；5)血统追踪 促进在愈合伤口中检测实验操纵的干细胞命运的技术；以及6) 新动物品系的产生和早衰的表观基因组诱导及基因组方法 恢复干细胞的年轻和多能性。我们的总体目标试图回答以下问题：1)如何 人们能否绘制出驱动年龄相关性伤口的关键代谢、表观遗传和细胞受体干细胞通路 治愈功能障碍？；2)干细胞导向的多成分有哪些可治疗的结节？ 在这些途径中的组合靶向；以及3)哪些因素可能会影响修复 创伤愈合和支持生理性皮肤的强大和再生干细胞驱动的反应 维护和健康？这一努力的成功可能会对理解衰老是如何 细胞可以恢复到正常组织完整性和再生潜力所隐含的功能活力。

SUMMARY Chronic ulcers, defined as wounds that fail to heal within a three-month period, are associated with age-related dysfunction in skin stem cells that not only has potential to blunt tissue repair, but also accounts for skin fragility, atrophy, and the "aging phenotype" that itself has clinical as well as psychosocial implications. Non-healing ulcers in aging individuals represent a multibillion dollar burden in the United States and to society globally, both through utilization of health care resources as well as through reduction in productivity. Nonetheless, it is recognized that "the basic biology and the influence of age-associated changes on wound healing are poorly understood, and there are numerous research questions still to be answered". To address this important issue, we have 1) assembled a highly collaborative and multidisciplinary team of investigators with established track records in skin pathology, regenerative and stem cell biology, wound healing, bioinformatics, and the pathobiology of aging; 2) leveraged the resources of seven Harvard Institutions to develop a unified and state- of-the-art approach to decipher the role skin stem cell deficiency in age-related defective wound healing; and 3) generated data-based hypotheses and identified inter-project synergies that will maximize productivity and translational focus. Our fundamental hypothesis is that identification and interrogation of three major, inter- related, and therapeutically targetable/reprogrammable pathways relevant to age-related skin stem cell dysfunction, a) metabolic, b) epigenetic, and c) membrane transporter/receptor, will pave the way for combinatorial (multicomponent) therapies necessary for more robust healing and regenerative responses to skin injury. We will pursue this goal through six strategies that have been developed by the key personnel of this PPG: 1) discovery of biomarkers for epidermal and dermal stem cell identification and manipulation; 2) determination of metabolic regulators required for epidermal progenitor activity and maintenance; 3) identification of novel epigenetic pathways that govern skin stem cell function and vitality; 4) development and evaluation of unique murine models that permit study of human wound healing in vivo; 5) deployment of lineage tracking technologies that facilitate detection of experimentally-manipulated stem cell fate in healing wounds; and 6) generation of new animal strains and for epigenomic induction of premature aging and methods for genomic restoration of stem cell youth and pluripotency. Our overall aims seek to answer the following questions: 1) How can one map the key metabolomic, epigenetic, and cell receptor stem cell pathways that drive age-related wound healing dysfunction?; 2) What are the therapeutically-accessible nodes for stem cell-directed multicomponent combinatorial targeting within these pathways?; and 3) What are the agents that likely will affect restoration of robust and regenerative stem cell-driven responses to wound healing and support physiologic cutaneous maintenance and health? Success in this endeavor could be transformative in understanding how aged stem cells may be restored to functional vigor implicit to normal tissue integrity and regenerative potential.