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Tissue Vascularization Using Blood- or Bone-Marrow-derived Progenitor Cells

使用血液或骨髓来源的祖细胞进行组织血管化

基本信息

批准号：
8130783
负责人：
Joyce E. Bischoff
金额：
$ 57.61万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-26 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8130783
关键词：
Advanced Development Anastomosis - action Area Autologous Biochemical Biological Models Blood Blood Circulation Blood Vessels Blood flow Bone Marrow Bone Marrow Cells CD34 gene Cardiac Cells Collaborations Complex Cutaneous Data Development Extracellular Matrix Firefly Luciferases Fluorescence Future Goals Heart Hour Human Human Ubiquitin Immunodeficient Mouse Implant In Situ In Vitro Ischemia Israel Laboratories Lentivirus Vector Magnetic Resonance Imaging Mechanics Medical center Modeling Monitor Myocardial Ischemia Myocardium Natural regeneration Organ Patients Perfusion Phenotype Process Proteins Publishing Radiology Specialty Recovery Regenerative Medicine Signal Transduction Site Smooth Muscle Stem cells System Techniques Technology Testing Time Tissue Engineering Tissues Ubiquitin C Vascular blood supply Vascularization Wound Healing base cell type design immunodeficient mouse model implantation in vivo in vivo Model matrigel prevent promoter public health relevance regenerative repaired scaffold tissue regeneration vascular tissue engineering vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): Our goal is to build vascular networks from human endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs) to re-build damaged tissues and organs. We and others have shown that human EPCs and SMPCs can be obtained from blood or bone marrow and expanded in the laboratory without difficulty. Our published and preliminary data demonstrate the vasculogenic capability of these cells in vivo using a Matrigel model and immunodeficient mice. In the future, we envision use of a patient's own EPCs and SMPCs for a variety of tissue-engineering (TE) applications and for in situ regeneration of vascular networks in ischemic tissue. For tissue- engineering (TE), vascular networks created from EPCs/SMPCs would be incorporated into tissue- engineered constructs in vitro such that upon implantation in vivo, anastomoses with the host circulation occur rapidly to establish blood flow. For tissue regeneration in situ, EPCs/SMPCs would be delivered to the site in vivo where they will undergo vasculogenesis, as we have demonstrated can occur in an in vivo Matrigel model. Our overall hypothesis is that EPCs and SMPCs applied to either a tissue-engineered (TE) organ or in situ to ischemic tissue will establish an adequate blood supply and thereby promote resident cells to undergo appropriate tissue development and regeneration. In this proposal, we will determine key parameters to accelerate the vasculogenic process to a time frame of 24-48 hours using the in vivo model we have established with human EPCs and SMPCs. Next, we will test the ability of vascular networks preformed in vitro within biodegradable scaffolds to form anastomoses with the host circulation upon implantation in vivo. Finally, we will test whether EPC/SMPCs will undergo vasculogenesis in ischemic myocardium and if so, evaluate the effect on recovery of the heart. In summary, we envision our two-cell system as an enabling technology that can be applied to many different tissues/organs wherein functional blood vessels are needed. We also view cell-based regenerative approaches as a continuum - from TE in which autologous cells seeded onto scaffold materials are stimuated by biochemical and mechanical forces to form tissue, to in situ tissue regeneration in which endogenous cellular repair processes are enhanced by a number of different mechanisms. Along this continuum, the timing and degree of vascularization will be a critical component for rebuilding complex tissues. Public Health Relevance Statement (provided by applicant): Our goal is to determine if vascular networks created from blood- or bone marrow-derived endothelial and smooth muscle progenitor cells will alleviate ischemia and promote tissue repair. In essence we are testing whether jump-starting the vascularization process with two highly purified and defined cell types will augment and/or accelerate the endogenous repair and regenerative mechanisms. We propose that this two-cell system is an enabling technology that can be applied to many different tissues and organs wherein functional blood vessels are needed. This proposal will focus on repair of ischemic myocardium, but we envision that our strategy for tissue vascularization will be applicable to tissue-engineering and to many aspects of regenerative medicine.

描述(由申请人提供)：我们的目标是从人内皮祖细胞和平滑肌祖细胞构建血管网络，以重建受损的组织和器官。我们和其他人已经证明，人的EPC和SmPC可以从血液或骨髓中获得，并在实验室中毫不费力地进行扩增。我们已发表的初步数据证明了这些细胞在Matrigel模型和免疫缺陷小鼠体内的血管生成能力。在未来，我们设想将患者自己的内皮祖细胞和SmPC用于各种组织工程(TE)应用和缺血组织中血管网络的原位再生。对于组织工程(TE)，由内皮祖细胞/间充质干细胞形成的血管网络将在体外被整合到组织工程构建物中，以便在体内植入后，迅速与宿主循环吻合以建立血液流动。对于原位组织再生，内皮祖细胞/基质干细胞将被输送到体内部位，在那里它们将经历血管生成，正如我们已经证明的那样，可以在体内Matrigel模型中发生。我们的总体假设是，无论是应用于组织工程(TE)器官还是原位应用于缺血组织，内皮祖细胞和SMPC都将建立足够的血液供应，从而促进常驻细胞经历适当的组织发育和再生。在这项提案中，我们将使用我们用人内皮祖细胞和SmPC建立的体内模型来确定将血管生成过程加速到24-48小时的时间框架的关键参数。接下来，我们将测试在生物可降解支架内体外预制的血管网络在体内植入后与宿主循环形成吻合的能力。最后，我们将测试EPC/SmPC是否会在缺血心肌中发生血管生成，如果是，评估其对心脏恢复的影响。总而言之，我们设想我们的双细胞系统是一种使能技术，可以应用于许多不同的组织/器官，其中需要功能血管。我们还将基于细胞的再生方法视为一个连续体-从种植到支架材料上的自体细胞通过生化和机械力刺激形成组织的TE，到通过多种不同机制促进内源性细胞修复过程的原位组织再生。沿着这一连续体，血管形成的时机和程度将是重建复杂组织的关键组成部分。公共卫生相关声明(由申请者提供)：我们的目标是确定由血液或骨髓来源的内皮和平滑肌前体细胞建立的血管网络是否将缓解缺血并促进组织修复。本质上，我们正在测试两种高度纯化和明确的细胞类型启动血管形成过程是否会增强和/或加速内源性修复和再生机制。我们认为，这种双细胞系统是一种使能技术，可以应用于许多不同的组织和器官，其中需要功能血管。这项建议将重点放在缺血心肌的修复上，但我们设想我们的组织血管形成策略将适用于组织工程和再生医学的许多方面。