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

• 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
• 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

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.

骨关节炎是一种与软骨和关节功能障碍相关的衰弱性疾病，由以下原因引起： 创伤或衰老严重影响患者的生活质量，导致每年的负担 大约150亿美元用于美国医疗保健。软骨再生本质上是低效的 并且仍然是一个未满足的医疗需求，增加了关节炎的发展倾向 状况。已利用基于细胞的治疗方法来修复局灶性软骨缺陷 自体成体软骨细胞或成体间充质干细胞（MSC），但成功有限 由于劣质纤维软骨的生成和细胞的缺乏。丰富的自体来源 因此，像人类诱导多能干细胞 (hiPSC) 一样，对工程设计具有吸引力 软骨。此外，从人类 iPSC 中生成发育“年轻”的软骨细胞 类似于新生儿或幼年软骨细胞，预计具有更高的再生能力 比成人软骨细胞的潜力。因此，本研究计划的目的是产生 来自同一健康或 OA 供体的 iPSC 和 MSC 并比较它们的软骨潜力 体外再生和大鼠模型骨软骨缺损的再生。为此，主要 进步将是产生无足迹的人类 iPSC，即不使用病毒载体 永久整合到基因组中。使用合成 mRNA 将能够产生安全的 和临床相关的 hiPSC。此外，我们最近开发了一种有效的方法 指导人类 iPSC (hiPSC) 向软骨细胞（或软骨祖细胞）分化 使用短暂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相关 能力。其次，我们将优化仿生水凝胶支架以使其成熟和 植入人类 iPSC 和 hMSC 衍生的软骨细胞。第三，潜力 人类 iPSC 和 hMSC 衍生的软骨细胞修复局灶性软骨缺损的能力将在 手术诱导骨软骨缺损的大鼠模型以及长期安全性研究 老鼠。总的来说，这些研究将有助于评估并提供机械理解 基于 hiPSC 的细胞疗法是否优于基于 hMSC 的疗法以及 成功完成可以为进一步开发临床适用的iPSC提供动力 局灶性软骨损伤的基础治疗。

项目成果

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

• DOI: 10.1002/adma.202101966
• 发表时间: 2021-09-09
• 期刊: ADVANCED MATERIALS
• 影响因子: 29.4
• 作者: Indana, Dhiraj;Agarwal, Pranay;Chaudhuri, Ovijit
• 通讯作者: Chaudhuri, Ovijit