Removal of Senescent Cells for Adipose-derived Stem Cell Transplants

去除衰老细胞以进行脂肪干细胞移植

• 批准号: 9294895
• 负责人: Allyson K Palmer
• 金额: $ 3.79万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294895
• 关键词: AP20187; Adipocytes; Adipose tissue; Age; Aging; Animals; Atherosclerosis; Autologous; Bone Marrow Transplantation; Cardiovascular Diseases; Cataract; Cell Aging; Cell Count; Cell Culture Techniques; Cell Transplants; Cells; Clinical; Clinical Trials; Development; Diabetes Mellitus; Disease; Elderly; Engraftment; Environment; Excision; Failure; Fatty acid glycerol esters; Functional disorder; Goals; Growth Factor; Harvest; Individual; Inflammatory; Intervention; Kidney; Knowledge; Laboratories; Mesenchymal Stem Cells; Metabolic; Modeling; Mus; Natural regeneration; Neurodegenerative Disorders; Normal Cell; Obesity; Organ; Outcome; Pathologic; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Play; Population; Preparation; Public Health; Regenerative Medicine; Research; Role; Seeds; Sirolimus; Skin; Skin wound; Soil; Solid; Source; Stem cell transplant; Stem cells; System; Testing; Therapeutic; TimeLine; Tissues; Translating; Transplant Recipients; Transplantation; adult stem cell; adult stem cell transplantation; age related; aged; cell age; cell growth; cell type; cytokine; experience; experimental study; frailty; implantation; improved; improved outcome; inflammatory milieu; innovation; insight; interest; kinase inhibitor; mouse model; novel; novel therapeutic intervention; older patient; patient population; progenitor; public health relevance; regenerative; repaired; sarcopenia; senescence; stem cell technology; success; wasting; wound closure

DESCRIPTION (provided by applicant): Adult stem cell transplantation is an emerging therapeutic strategy with wide potential to treat numerous age-related disorders such as cardiovascular disease, diabetes, and neurodegenerative disease. However, very little research has explored the causes of decreased efficacy of stem cell transplantation in the elderly population, who may have the most to gain from these new therapeutic strategies. Our laboratory is attacking this question using a 'seed vs. soil' model, asking whether an inherent dysfunction in the transplanted cells, the 'seed', or an inhospitable aged host microenvironment, the 'soil', is responsible for decreased therapeutic potential. We are specifically interested in te role of senescent cells in this interaction between 'seed' and 'soil' in transplantation. Senescent cells are growth-arrested cells that remain metabolically active and have been shown to promote a pro-inflammatory environment through the secretion of various cytokines, growth factors, and matrix remodeling factors, collectively known as the senescence-associated secretory phenotype (SASP). With aging, senescent cell numbers increase throughout the body, and are thought to contribute to many age-related diseases. Therefore, the long term goal of this study is to determine the role of increasing senescent cell burden in transplant failure. Our hypothesis is that removal of senescent cells from either the donor cells or the recipient mouse will improve transplant outcomes. We also hypothesize that by using pharmacologic agents shown to limit the SASP, namely rapamycin and Janus-activated kinase (Jak) inhibitors, we can limit the detrimental effects of senescent cells and improve transplant outcomes. To test these hypotheses, we will pursue the following specific aims: AIM 1. Soil: Prepare the transplant microenvironment by removing senescent cells in recipient mice. AIM 2. Seed: Prepare the cells to be transplanted by removing senescent cells from donor ADSCs. AIM 3. Pharmacologic Intervention: Determine the effect of SASP inhibition in the recipient on efficacy of autologous ADSC transplant. In these studies, we will use a novel mouse model in which senescent cells can be selectively cleared from the mouse by administration of a drug that does not affect normal cells. We will study the transplantation of adipose-derived stem cells on skin wounds in mice, allowing easy tracking of stem cell engraftment and incorporation into regenerating tissue, as well as wound closure. Senescent cells will be cleared either from the recipient prior to transplantation of adipose-derived stem cells, to prepare the host environment (the 'soil') for transplant, or senescent cells will be cleared from mice before isolation of stem cells, to prepare the transplanted cells (the 'seed'). Alternatively, recipient animals will be treated with SASP-limiting agents rapamycin or Jak inhibitors prior to transplantation. A timeline for these experiments can be found at the end of the Research Strategy section of this proposal. The insights we gain into the role of senescent cells in stem cell transplantation may be hugely beneficial to the development of new therapeutic strategies that allow the application of emerging stem cell technologies to the elderly population.

描述（由申请人提供）：成年干细胞移植是一种新兴的治疗策略，具有广泛的治疗与年龄有关的疾病的潜力，例如心血管疾病，糖尿病和神经退行性疾病。但是，很少的研究探讨了干细胞移植在老年人群中的疗效降低的原因，他们可能从这些新的治疗策略中获得最大的收益。我们的实验室正在使用“种子与土壤”模型来攻击这个问题，询问移植细胞中固有的功能障碍，“种子”或陷入困境的老年宿主微环境，即“土壤”，导致治疗潜力降低。我们特别对衰老细胞在移植中的“种子”和“土壤”之间的相互作用中的作用特别感兴趣。衰老 细胞是生长序列的细胞，通过分泌各种细胞因子，生长因子和基质重塑因子（共同称为衰老相关的分泌表型（SASP）），可以通过分泌各种细胞因子，生长因子和基质重塑因子来促进促炎环境。随着衰老的衰老，衰老细胞数量在整个人体中增加，被认为会导致许多与年龄有关的疾病。因此，这项研究的长期目标是确定增加衰老细胞负担在移植衰竭中的作用。我们的假设是，从供体细胞或受体小鼠中去除衰老细胞将改善移植结果。我们还假设，通过使用显示限制SASP的药理学剂，即雷帕霉素和Janus激活的激酶（JAK）抑制剂，我们可以限制衰老细胞的有害作用并改善移植结果。为了检验这些假设，我们将追求以下特定目标：目标1。土壤：通过去除受体小鼠中的衰老细胞来准备移植微环境。目标2。种子：准备通过从供体ADSC中去除衰老细胞移植的细胞。 AIM 3。药理干预：确定SASP抑制对受体自体ADSC移植功效的影响。在这些研究中，我们将使用一种新型的小鼠模型，在该模型中，可以通过给予不影响正常细胞的药物从小鼠中选择性地清除衰老细胞。我们将研究小鼠皮肤伤口上脂肪衍生的干细胞的移植，从而轻松跟踪干细胞植入并掺入再生组织以及伤口闭合。在移植脂肪衍生的干细胞之前，将从接受者中清除衰老细胞，以准备移植的宿主环境（“土壤”），或者将从小鼠分离之前从小鼠中清除衰老细胞，以制备干细胞，以制备准备。 移植细胞（“种子”）。另外，将在移植前用SASP限制剂雷帕霉素或JAK抑制剂治疗受体动物。这些实验的时间表可以在本提案的研究策略部分的末尾找到。我们对衰老细胞在干细胞移植中的作用的见解可能对发展新的治疗策略的发展极为有益，这些策略允许将新兴的干细胞技术应用于老年人群。