Autologous Stem Cell-Based Tissue Engineered Vascular Grafts

描述（由申请人提供）：由于目前的临床选择不可靠，因此美国每年进行的近100万例冠状动脉搭桥术、外周动脉搭桥术和动静脉通路移植物手术非常需要成功的血管移植物。该R21提案的总体目标是通过解决实际实施的关键问题和阻碍当前范例成功的限速障碍，开始我们新型、自体、基于干细胞的组织工程血管移植物（TEVG）的临床转化过程。该提案将重点关注脂肪源性干细胞（ADSC）的使用，因为在有需要的患者群体中，脂肪的分离和可用性相对容易。本提案将解决以下重要问题：A）在典型的单次收获中从患者分离的自体成体ADSC数量有限。产生成功的TEVG所需的ADSC接种密度的下限是多少？B）年龄和性别都被证明会影响心血管疾病的发展和治疗效果。使用来自所有患者的ADSC的基于干细胞的TEVG是否可行，或者某些因素（例如，男性或女性，超过一定年龄的患者）排除这种治疗？因此，该2年提案的两个具体目标是：1）评估ADSC接种密度对在大鼠模型中测试的TEVG构建体的性能的影响;以及2）评估相同性别的大鼠模型中供体年龄和性别对基于人细胞的TEVG构建体的体内性能的影响。这项工作的预期结果是成功开发基于人类干细胞的TEVG的重要一步，使其更接近临床转化。据我们所知，没有其他研究已经解决了临床实用性的关键问题，例如这里要解决的那些问题，用于开发基于干细胞的人类TEVG。

DESCRIPTION (provided by applicant): There is a significant need for a successful vascular graft for the nearly one million aortocoronary bypass, peripheral arterial bypass, and arterio-venous access graft procedures performed each year in the US, as current clinical options are unreliable. The overall goal of this R21 proposal is to begin the process of clinical translation o our novel, autologous, stem cell-based tissue engineered vascular graft (TEVG) by addressing critical issues of practical implementation and rate-limiting barriers that have prevented current paradigms from being successful. This proposal will focus on use of adipose-derived stem cells (ADSCs), given the relative ease of isolation and availability of fat in the patient population in need. The following important issues/questions will be addressed in this proposal: A) Autologous adult ADSCs isolated in a typical single harvest from a patient are limited in number. What is the lower bound of ADSC seeding density necessary to yield a successful TEVG? B) Age and sex have both been shown to influence cardiovascular disease development and treatment efficacy. Will a stem cell-based TEVG using ADSCs from all patients be feasible, or will certain factors (e.g., male or female sex, patients beyond a certain age) preclude this therapy? Accordingly, the two specific aims of this 2-year proposal are: 1) Assess the effect of ADSC seeding density on the performance of TEVG constructs tested in a rat model; and 2) Assess the effect of donor age and sex in a rat model of the same sex on in-vivo performance of human cell-based TEVG constructs. The expected outcome of this work is an important step toward the successful development of a human stem cell-based TEVG, moving it significantly closer to clinical translation. No other study, to our knowledge, has addressed critical issues of clinical practicality, such as those to be addressed here, for the development of a human, stem cell-based TEVG.