Adipose Stromal Cells and Vasculogenesis: Tissue Perfusion and Islet Survival

脂肪基质细胞和血管发生：组织灌注和胰岛存活

• 批准号: 7934224
• 负责人: KEITH LEONARD MARCH
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934224
• 关键词: 3-Dimensional; Acute; Address; Adipocytes; Adipose tissue; Affect; Aging; Allogenic; Animals; Apoptosis; Apoptotic; Autologous; Biological Models; Blood Vessels; Blood flow; Cell Proliferation; Cell Survival; Cell Therapy; Cells; Cellular Structures; Cerebral Ischemia; Characteristics; Chondrocytes; Coupled; Cutaneous; Data; Devices; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Disease; Effectiveness; Elderly; Endothelial Cells; Environment; Evaluation; Exhibits; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Goals; Growth Factor; Health Care Costs; Hematopoietic; Hepatocyte Growth Factor; Hindlimb; Human; Hyperglycemia; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Immunocompromised Host; Impairment; Implant; In Vitro; Individual; Insulin-Dependent Diabetes Mellitus; Investigation; Ischemia; Islets of Langerhans; Islets of Langerhans Transplantation; Laboratories; Lead; Mediating; Mesenchymal; Metabolic Diseases; Methods; Modeling; Modification; Molecular; Mus; Muscle Fibers; Myocardial; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Osteoblasts; Oxygen; Pathway interactions; Patients; Perfusion; Pericytes; Physiological; Play; Population; Process; Property; Proteins; Publishing; Relative (related person); Role; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Skeletal Muscle; Source; Specific qualifier value; Stem cells; Stromal Cells; Structure; Suction Lipectomy; Supplementation; System; Testing; Therapeutic; Tissue Survival; Tissues; Transplantation; United States Department of Veterans Affairs; Vascular Endothelial Growth Factors; Vascular blood supply; Vascularization; Veterans; Work; Wound Healing; aged; cell preparation; diabetic; diabetic patient; functional disability; human subject; implantation; improved; in vivo; insight; irradiation; islet; network models; novel; pancreatic islet function; paracrine; postnatal; research study; response; stem; subcutaneous; two-dimensional; vasculogenesis

DESCRIPTION (provided by applicant): The description of pluripotent cells in adipose tissue has led to the concept that adipose tissue may provide a novel autologous source of cells with significant potential for tissue modification. Such adipose stromal cells (ASCs) can be obtained in large quantities, in the range of 108 to 109 cells, following routine liposuction of subcutaneous adipose tissue. This ready accessibility in turn has suggested the notion that they might provide for a particularly feasible and attractive form of autologous cell therapy. Work in our laboratory supported by our prior Merit Review, as well as that of others, has clearly demonstrated that ASCs can increase tissue perfusion and limit ischemic tissue damage in several circumstances, by secretion of angiogenic and anti-apoptotic factors. Recently, we have also found that ASCs are capable of stabilizing endothelial networks in vitro as well as robustly synergizing with endothelial cells (EC) to participate in the in vivo formation of new vessels. Additionally, this observation led us to hypothesize that the synergy between ASC and EC would provide a practical approach to tissue vascularization for implants or regional ischemia. Our recent findings that ASCs in culture can promote sustained secretory function of pancreatic islets, and that ASCs assemble vascular networks when co-implanted with both endothelial cells and islets, has prompted us to further evaluate the mechanisms by which these cells assemble vessels and modulate islet responses. The overall hypothesis of this proposal is thus that ASCs are uniquely accessible and expandible pluripotent cells that have the capacity to differentiate along pathways giving rise to vascular mural cells, and which can facilitate in vivo vasculogenesis and cell survival in the context of implanted islets. The specific aims that will be pursued in order to test this hypothesis are 1.) Evaluate the mechanisms, dynamics, and key factors responsible for governing ASC-mediated vascular network formation by ECs in vitro and in vivo; 2.) Evaluate the capacity of ASC or ASC subpopulations to support pancreatic islet function in vitro and in vivo by direct paracrine support; and to further preserve islet function by assembly of a chimeric human vascular network by ASC and EC in vivo; and 3.) Determine the effect of diabetes and aging on the competency of human ASCs to participate in chimeric vasculogenesis in vivo, and on the signalling function of the master angiogenic control factors, HIF-1a and HIF-1bin ASCs. This study will help to determine the extent to which ASC and EC co-transplantation can assist with tissue survival; and by using islet transplantation as a model, will permit an assessment of whether islet transplantation can be significantly augmented by ASCs and vascular networks which they can help to form. In addition, this study will clarify the potential of autologous ASC obtained from patients with diabetes to contribute to tissue survival via either paracrine effects or vascularization; and identify key molecular mechanisms underlying functional impairment of ASC in diabetes. Marked impairment in these functions would highlight the need for approaches involving either targeted modification of autologous ASC, or allogeneic ASC. PUBLIC HEALTH RELEVANCE: Our study will provide insight into how to use the stem cells located in fat tissue to assist in creating blood vessel structures to help provide blood supply to tissues that require it, and in particular to islets that are transplanted. Since we are working with cell preparation devices / methods that are appropriate for human use, the insights developed in this study will be directly translatable to Veterans. Specifically, we anticipate that the approaches we are studying will apply to Veterans that have problems due to poor blood flow; such as poor wound healing; and to diabetic Veterans who may be able to benefit from islet transplantation to treat or actually cure their diabetes. The findings from this study will point the way to optimized methods for transplanting islets along with cells that can assemble vascular structures; and will also determine whether cells from all patients can be used, or whether cells from younger or healthier patients must be explored, and why. Successful work to treat diabetes and diabetic vascular disease will markedly improve the effectiveness, and may indeed decrease longterm costs of healthcare in the Veterans Administration system.

描述（由申请人提供）： 对脂肪组织中多能细胞的描述引发了这样一个概念：脂肪组织可能提供一种新的自体细胞来源，具有组织修饰的巨大潜力。通过皮下脂肪组织的常规吸脂术，可以大量获得此类脂肪基质细胞（ASC），数量范围为 108 至 109 个细胞。这种现成的可及性反过来表明了这样一种观念，即它们可能提供一种特别可行且有吸引力的自体细胞疗法形式。我们实验室的工作得到了我们之前的优异评审以及其他人的支持，已经清楚地表明，ASC 在某些情况下可以通过分泌血管生成因子和抗凋亡因子来增加组织灌注并限制缺血性组织损伤。最近，我们还发现ASC能够在体外稳定内皮网络，并与内皮细胞（EC）强有力地协同参与体内新血管的形成。此外，这一观察结果使我们推测 ASC 和 EC 之间的协同作用将为植入物或局部缺血的组织血管化提供一种实用的方法。我们最近发现培养的 ASC 可以促进胰岛的持续分泌功能，并且 ASC 在与内皮细胞和胰岛共同植入时组装血管网络，这促使我们进一步评估这些细胞组装血管和调节胰岛的机制回应。因此，该提案的总体假设是，ASC 是独特的可接近和可扩展的多能细胞，具有沿着产生血管壁细胞的途径分化的能力，并且可以在植入的胰岛的情况下促进体内血管生成和细胞存活。为了检验这一假设，我们将追求的具体目标是 1.) 评估体外和体内 ECs 控制 ASC 介导的血管网络形成的机制、动力学和关键因素； 2.) 评估 ASC 或 ASC 亚群通过直接旁分泌支持在体外和体内支持胰岛功能的能力；并通过体内 ASC 和 EC 组装嵌合人血管网络来进一步保护胰岛功能； 3.) 确定糖尿病和衰老对人类 ASC 参与体内嵌合血管生成的能力以及对主要血管生成控制因子 HIF-1a 和 HIF-1bin ASC 的信号传导功能的影响。这项研究将有助于确定 ASC 和 EC 联合移植在多大程度上有助于组织存活；通过使用胰岛移植作为模型，将可以评估 ASC 和它们有助于形成的血管网络是否可以显着增强胰岛移植。此外，这项研究将阐明从糖尿病患者获得的自体 ASC 通过旁分泌效应或血管化促进组织存活的潜力；并确定糖尿病 ASC 功能损伤的关键分子机制。这些功能的明显损伤凸显了对涉及自体 ASC 或同种异体 ASC 的靶向修饰方法的需求。 公共卫生相关性： 我们的研究将深入了解如何使用位于脂肪组织中的干细胞来协助创建血管结构，以帮助为需要的组织，特别是移植的胰岛提供血液供应。由于我们正在研究适合人类使用的细胞制备设备/方法，因此本研究中形成的见解将直接转化为退伍军人。具体来说，我们预计我们正在研究的方法将适用于因血液流动不良而出现问题的退伍军人；例如伤口愈合不良；对于患有糖尿病的退伍军人来说，他们可能能够从胰岛移植中受益，以治疗或实际上治愈他们的糖尿病。这项研究的结果将为移植胰岛以及可组装血管结构的细胞的优化方法指明道路；还将确定是否可以使用来自所有患者的细胞，或者是否必须探索来自年轻或健康患者的细胞，以及原因。治疗糖尿病和糖尿病血管疾病的成功工作将显着提高有效性，并且确实可能​​降低退伍军人管理局系统的长期医疗保健成本。