Vascular Regeneration with Human Pluripotent Stem Cell-derived Vascular Cells and Engineering Approaches

人类多能干细胞来源的血管细胞的血管再生和工程方法

基本信息

批准号：
10548851
负责人：
Young-Sup Yoon
金额：
$ 49.15万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548851
关键词：
Alginates American Area Biocompatible Materials Biological Biomedical Engineering Blood Vessels Blood capillaries Cardiac Myocytes Cardiovascular Diseases Cell Culture System Cell Differentiation process Cell Lineage Cell Survival Cell Therapy Cell Transplantation Cell physiology Cells Clinical Clinical Trials Dependence Disease Effectiveness Encapsulated Endothelial Cells Engineering Functional disorder Gel Gelatin Generations Goals Hindlimb Histologic Human Hybrids Hydrogels Impairment Inflammatory Response Injectable Injections Intervention Ischemia Magnetic Resonance Imaging Measurement Methacrylates Microspheres Modeling Molecular Morbidity - disease rate Mus Myocardial Ischemia Operative Surgical Procedures Organ Outcome Patients Pericytes Peripheral arterial disease Polymers Population Protocols documentation Research Research Personnel Smooth Muscle Myocytes System Technology Therapeutic Therapeutic Effect Tissues Vascular Diseases Vascular regeneration Vascularization Virus adult stem cell arteriole blood vessel development cell type clinical application copolymer design disease prognosis expectation human embryonic stem cell human pluripotent stem cell improved in vivo induced pluripotent stem cell microCT mortality nano neovascularization next generation novel paracrine peptide amphiphiles poly(glycerol-sebacate)preclinical study regenerative therapy stem cells virtual

项目摘要

Project Summary Ischemic cardiovascular diseases are the leading causes of morbidity and mortality in the USA. Despite advancement in therapeutics, treating patients with severe conditions are still far from optimal. Recently, cell therapy emerged as a promising option for those advanced cases for which no interventional or surgical therapy is able to effectively revascularize the ischemic areas. Human pluripotent stem cells (hPSCs), which include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), have emerged as a promising candidate for vascular regeneration as they have strong target cell differentiation capacity as well as paracrine effects. Thus, investigators have developed various protocols to differentiate hPSCs into endothelial cell (EC)-lineage cells. We have developed a fully defined, xenogeneic ingredient-free cell culture system that can generate purified functional endothelial cells (ECs) at high yield. We further demonstrated that these hPSC-derived ECs (hPSC-ECs) have robust and prolonged vessel-forming activities in vivo. However, one of the caveats of this approach is that their contribution is mainly restricted to the capillary level without pericytes. For optimal vascularization, more stable and larger vessels are also necessary. In previous cell therapy studies, this aspect was virtually unaddressed. Therefore, we recently generated human PSC-derived SMCs (hPSC-SMCs) by using a defined culture system as well and observed their contribution to vessel formation as vascular pericytes and SMCs. Another important barrier for cell therapy is short-term survival of the transplanted cells. To overcome this problem, we and others have investigated bioengineered cell therapy and demonstrated its effectiveness for cell survival and function. However, uneven and localized distribution of the injected cells emerged as another problem. Recently, we have developed a novel biodegradable hybrid copolymer consisting of gelatin and poly glycerol sebacate (PGS), which was further made into a microbead form with alginate. We refer to this co- polymer as AlGPM. This hybrid polymer is biodegradable and elicits minimal inflammatory responses. Moreover, its microbead form promotes wide and homogeneous distribution of encapsulated cells in vivo. Accordingly, in this study, we will address two unmet needs of the current cell therapy for ischemic vascular disease. First, we will use both hPSC-ECs and hPSC-SMCs to induce formation of not only bare capillaries but also pericyte-covered capillaries and SMC-covered arterioles. Second, we will develop a new biomaterial that can enhance cell survival and distribution in vivo to maximize stable vessel formation and therapeutic effects. Specifically, we will investigate whether a combination of these two cell types with AlGPM hydrogel microbeads is able to exert the optimal effects on vascular regeneration. The long-term goal of this study is to develop clinically applicable regenerative therapy using hPSC-derived vascular cells combined with bioengineering technologies.

项目摘要缺血性心血管疾病是美国发病和死亡率的主要原因。尽管治疗疗法的进步，治疗严重疾病的患者远非最佳。最近，细胞对于那些没有介入或外科手术的晚期病例，治疗是一种有前途的选择治疗能够有效地血运重建缺血区域。人类多能干细胞（HPSC），包括人类胚胎干细胞（HESC）和人类诱导多能干细胞（HIPSC）已成为血管再生的有前途的候选者它们具有强大的靶细胞分化能力以及旁分泌作用。因此，调查人员有开发了各种方案，将HPSC区分为内皮细胞（EC）细胞。我们已经发展了一个完全定义的，异构成分的无细胞培养系统，可以产生纯化的功能性内皮细胞（EC）高产量。我们进一步证明了这些HPSC衍生的ECS（HPSC-EC）具有强大的体内长时间的血管形成活性。但是，这种方法的警告之一是他们的贡献主要仅限于无周细胞的毛细管水平。为了获得最佳血管化，更稳定和更大还需要船只。在先前的细胞疗法研究中，这方面几乎没有得到解决。所以，我们最近通过使用定义的培养系统生成了人类PSC衍生的SMC（HPSC-SMC）并观察到它们对血管形成的贡献是血管周细胞和SMC。细胞治疗的另一个重要障碍是移植细胞的短期存活。克服这个问题，我们和其他人研究了生物工程的细胞疗法，并证明了其有效性细胞存活和功能。但是，注射细胞的不均匀和局部分布出现为另一种问题。最近，我们开发了一种新型的可生物降解的杂种共聚物，由明胶和聚合物组成甲酸酯（PGS），该甘油被进一步制成带有藻酸盐的微粒形式。我们指的是这个共同聚合物作为ALGPM。该混合聚合物是可生物降解的，并且引起最小的炎症反应。而且，它的微粒形式促进了体内封装细胞的较宽和均匀分布。因此，在这项研究中，我们将解决当前细胞疗法的两种未满足的缺血需求血管疾病。首先，我们将同时使用HPSC-EC和HPSC-SMC诱导形成不仅是裸露的毛细血管也是周细胞覆盖的毛细血管和SMC覆盖的小动脉。第二，我们将开发一个新的可以在体内增强细胞存活和分布的生物材料，以最大化稳定的血管形成和治疗作用。具体来说，我们将研究这两种细胞类型是否与 ALGPM水凝胶微粒能够对血管再生产生最佳影响。长期这项研究的目标是使用HPSC衍生的血管细胞开发临床适用的再生治疗结合生物工程技术。