Evaluating the Potential of Human Induced Pluripotent Stem Cells (hiPSC) For Cartilage Repair

评估人类诱导多能干细胞 (hiPSC) 软骨修复的潜力

基本信息

批准号：
10204871
负责人：
Nidhi Bhutani
金额：
$ 43.54万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-05 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204871
关键词：
13 year old 3-Dimensional Activities of Daily Living Adolescent Adult Affect Aging Allogenic Arthritis Autologous Biochemical Biological Biology Biomechanics Biomimetics Blood Bone Marrow Cartilage Cartilage Diseases Cartilage injury Cell Therapy Cell Transplantation Cells Chondrocytes Chondroitin Sulfates Clinic Cues Data Defect Degenerative polyarthritis Development Elderly Engineering Exposure to Fibrocartilages Functional disorder Future Gene Expression Profile Generations Genome Growth Factor Health Healthcare Heparitin Sulfate Histologic Human Human Characteristics Hydrogels Immune Inferior Inflammation Inflammatory International Joints Medical Mesenchymal Stem Cells Messenger RNA Methodology Modeling Molecular Morbidity - disease rate Mus Neonatal Nude Rats Operative Surgical Procedures Pain management Patients Peripheral Blood Mononuclear Cell Polyethylene Glycols Population Procedures Property Protocols documentation Quality of life Rattus Regenerative Medicine Replacement Arthroplasty Research Proposals Resistance Series Side Site Societies Source Surgical Models System Techniques Testing Tissues Transforming Growth Factor beta Trauma Viral Vector articular cartilage base cartilage regeneration cartilage repair clinical application clinically relevant comparative efficacy design differentiation protocol experimental study hydrogel scaffold implantation in vitro regeneration induced pluripotent stem cell innovation insight novel osteochondral tissue regeneration potential repaired response safety study scaffold sex stem cell differentiation stem cell therapy stem cells success tissue repair transcriptome tumor tumorigenic

项目摘要

Osteoarthritis is a debilitating condition associated with cartilage and joint dysfunction caused by trauma or aging that severely affects patients' quality of life resulting in a yearly burden of approximately 15 billion dollars on US healthcare. Cartilage regeneration is inherently inefficient and remains an unmet medical need that increases the propensity for development of arthritic conditions. Cell-based therapeutic approaches for repairing focal cartilage defects have utilized autologous adult chondrocytes or adult mesenchymal stem cells (MSC) but with limited success due to generation of inferior fibrocartilage and paucity of cells. An abundant autologous source like human induced pluripotent stem cells (hiPSC) is therefore attractive for engineering cartilage. Additionally, generation of developmentally `younger' chondrocytes from human iPSC akin to the neonatal or juvenile chondrocytes are expected to possess a higher regeneration potential than adult chondrocytes. The aim of this research proposal is therefore to generate iPSC and MSC from the same healthy or OA donor and comparing their potential for cartilage regeneration in vitro and in an osteochondral defect in a rat model. Towards this end, a major advance will be the generation of footprint-free human iPSC i.e. without the use of viral vectors that permanently integrate into the genome. Use of synthetic mRNA will allow generation of safe and clinically relevant hiPSC. Additionally, we have recently developed an efficient methodology to direct human iPSC (hiPSC) differentiation towards chondrocytes (or chondroprogenitor cells) using transient exposure to a series of growth factors. We will define molecular and functional characteristics of hiPSC- and hMSC-derived chondrocytes to relate with their functional capabilities. Secondly, we will optimize a biomimetic hydrogel scaffold for the maturation and implantation of human iPSC- and hMSC-derived chondrocytes. Thirdly, the potential of the human iPSC- and hMSC-derived chondrocytes to repair a focal cartilage defect will be tested in a rat model of surgically induced osteochondral defect along with long-term safety studies in mice. Collectively, these studies will help evaluate and provide a mechanistic understanding of whether a hiPSC-based cellular therapy will be superior to hMSC-based therapy and successful completion can provide the impetus to further develop a clinically applicable iPSC- based therapy for focal cartilage injury.

骨关节炎是与软骨和关节功能障碍有关的令人衰弱的疾病创伤或衰老严重影响患者的生活质量，导致年度负担美国医疗保健约150亿美元。软骨再生本质上效率低下并且仍然是未满足的医疗需求，增加了关节炎发展的倾向状况。利用了基于细胞的修复焦点软骨缺陷的治疗方法自体软骨细胞或成年间充质干细胞（MSC），但成功有限由于细胞的下纤维化和细胞的较弱而产生。丰富的自体源像人类诱导的多能干细胞（HIPSC）一样，对工程具有吸引力软骨。此外，人类IPSC的发育生成“年轻”的软骨细胞类似于新生儿或青少年软骨细胞的再生比成年软骨细胞的潜力。因此，该研究建议的目的是产生 IPSC和MSC来自相同的健康或OA供体，并比较它们的软骨潜力大鼠模型中的体外和骨软骨缺损的再生。为此，一个专业前进将是无足迹的人IPSC的产生，即不使用病毒载体这将永久整合到基因组中。使用合成mRNA将允许生成安全和临床相关的HIPSC。此外，我们最近开发了一种有效的方法将人IPSC（HIPSC）指向软骨细胞（或软骨元基因细胞）的分化使用瞬时暴露于一系列生长因子。我们将定义分子和功能 HIPSC和HMSC衍生的软骨细胞的特征与其功能有关功能。其次，我们将优化成熟和成熟的仿生水凝胶支架人IPSC和HMSC衍生的软骨细胞的植入。第三，潜力人IPSC和HMSC衍生的软骨细胞以修复焦点软骨缺陷。通过手术诱导骨软骨缺陷的大鼠模型以及长期安全研究老鼠。总的来说，这些研究将有助于评估并提供对机械的理解基于HIPSC的细胞疗法是否优于基于HMSC的治疗和成功完成可以提供动力，以进一步开发临床适用的IPSC- 基于局灶性软骨损伤的治疗。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A dysfunctional TRPV4-GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity.

DOI：
10.1038/s41551-021-00691-3
发表时间：
2021-12
期刊：
Nature biomedical engineering
影响因子：
28.1
作者：
Agarwal P;Lee HP;Smeriglio P;Grandi F;Goodman S;Chaudhuri O;Bhutani N
通讯作者：
Bhutani N

Encapsulated Mesenchymal Stromal Cell Microbeads Promote Endogenous Regeneration of Osteoarthritic Cartilage Ex Vivo.

DOI：
10.1002/adhm.202002118
发表时间：
2021-04
期刊：
ADVANCED HEALTHCARE MATERIALS
影响因子：
10
作者：
Sahu, Neety;Agarwal, Pranay;Grandi, Fiorella;Bruschi, Michela;Goodman, Stuart;Amanatullah, Derek;Bhutani, Nidhi
通讯作者：
Bhutani, Nidhi

Viscoelasticity and Adhesion Signaling in Biomaterials Control Human Pluripotent Stem Cell Morphogenesis in 3D Culture