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

• 批准号: 7903361
• 负责人: Joyce E. Bischoff
• 金额: $ 55.48万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-26 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903361
• 关键词: Advanced Development; Anastomosis - action; Area; Autologous; Biochemical; Biological Models; Blood; Blood Circulation; Blood Vessels; Blood flow; Bone Marrow; Bone Marrow Cells; 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

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）： 我们的目标是利用人内皮祖细胞（EPC）和平滑肌祖细胞（SMPC）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，人类 EPC 和 SMPC 可以从血液或骨髓中获得，并在实验室中毫无困难地进行扩增。我们发表的初步数据证明了使用基质胶模型和免疫缺陷小鼠体内这些细胞的血管生成能力。未来，我们设想将患者自身的 EPC 和 SMPC 用于各种组织工程 (TE) 应用以及缺血组织中血管网络的原位再生。对于组织工程（TE），由 EPC/SMPC 创建的血管网络将被纳入体外组织工程构建体中，以便在植入体内后，与宿主循环迅速发生吻合以建立血流。对于原位组织再生，EPC/SMPC 将被递送至体内部位，在那里它们将进行血管生成，正如我们已经证明可以在体内基质胶模型中发生的那样。我们的总体假设是，将 EPC 和 SMPC 应用于组织工程（TE）器官或原位缺血组织将建立足够的血液供应，从而促进驻留细胞进行适当的组织发育和再生。在本提案中，我们将使用我们用人类 EPC 和 SMPC 建立的体内模型来确定关键参数，以将血管生成过程加速到 24-48 小时的时间范围。接下来，我们将测试在生物可降解支架内体外形成的血管网络在植入体内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进行血管生成，如果是的话，评估对心脏恢复的影响。总之，我们设想我们的两细胞系统作为一种使能技术，可以应用于需要功能性血管的许多不同组织/器官。我们还将基于细胞的再生方法视为一个连续体 - 从 TE（通过生化和机械力刺激种植在支架材料上的自体细胞形成组织），到原位组织再生（通过许多不同的机制增强内源性细胞修复过程）。沿着这个连续体，血管化的时间和程度将是重建复杂组织的关键组成部分。 公共卫生相关性声明（由申请人提供）：我们的目标是确定由血液或骨髓来源的内皮细胞和平滑肌祖细胞创建的血管网络是否会减轻缺血并促进组织修复。本质上，我们正在测试用两种高度纯化和明确的细胞类型启动血管化过程是否会增强和/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，可以应用于需要功能性血管的许多不同组织和器官。该提案将重点关注缺血心肌的修复，但我们预计我们的组织血管化策略将适用于组织工程和再生医学的许多方面。