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

基本信息

批准号：
8391612
负责人：
KEITH LEONARD MARCH
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8391612
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 public health relevance research study response stem subcutaneous two-dimensional vasculogenesis

项目摘要

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.