Induced pluripotent stem cell therapy for degenerated IVD

诱导多能干细胞治疗退化性 IVD

• 批准号: 10388144
• 负责人: Dmitriy Sheyn
• 金额: $ 11.92万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388144
• 关键词: Acute; Address; Adult; Animal Model; Antiinflammatory Effect; Area; Attenuated; Back Pain; Biology; Bone Tissue; Cartilage; Cell Survival; Cell Therapy; Cells; Child; Chronic; Cicatrix; Data; Development; Disease; Dyes; Educational workshop; Embryonic Development; Environment; Family suidae; Fibrosis; Funding; Gene Delivery; Gene Expression; Gene Expression Profiling; Genetic; Goals; Harvest; Histologic; Human; IL8 gene; Image; Imaging technology; Immunoassay; Immunology; Inflammation; Inflammatory; Injections; Injury; Institute of Medicine (U.S.); Interferon Type II; Interleukin-1 beta; Interleukin-17; Interleukin-6; Intervertebral disc structure; Knowledge; Label; Leadership; Link; Magnetic Resonance Imaging; Measures; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Modeling; Molecular Biology; Monitor; Musculoskeletal; Natural regeneration; Needles; Organ Culture Techniques; Outcome Study; Pain; Parents; Pathogenesis; Patients; Peptides; Phenotype; Physiological; Play; Population; Positioning Attribute; Process; Proteins; Publications; Puncture procedure; Quantitative Reverse Transcriptase PCR; Regenerative Medicine; Rejuvenation; Reporting; Research; Research Personnel; Role; Seasons; Solid; Source; Supervision; Symptoms; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissue Engineering; Training; Training Programs; Vertebral column; Visit; age related; alternative treatment; base; career; cell type; cytokine; design; disc regeneration; experience; hands on research; immunoregulation; improved; in vivo; in vivo Model; induced pluripotent stem cell; innovation; intervertebral disk degeneration; notochord; novel; nucleus pulposus; preclinical study; quantitative imaging; regeneration potential; soft tissue; stem cell therapy; stem cells; targeted treatment; tissue regeneration; transcriptome sequencing

Project Summary/abstract As many as 80% of the adult population experience back pain at some point in their lifetimes. Previous studies have indicated a link between back pain and intervertebral disc (IVD) degeneration in 40% of patients. Despite decades of research, robust therapies targeting underlying causes rather than symptoms are still in the earliest stages of development. Thus, there is an urgent need for alternative treatment, such as stem cell therapy, focused on correcting the underlying pathogenesis of DDD. Dr. Sheyn’s goal is to develop his academic career in musculoskeletal tissue engineering and stem cell therapy field, focusing on spine therapeutics. He has received excellent training in stem cell manipulation and gene delivery, in vivo models, bone tissue engineering and molecular biology. He has established solid track record of publications in the field and demonstrated strong capacity to conduct innovative research. The proposed training program is designed to build on Dr. Sheyn’s background and strengthen his expertise in specific areas most relevant to IVD therapeutics. Under the leadership and sponsorship of Dr. Clive Svendsen, the director of the Cedars-Sinai Regenerative Medicine Institute, Dr. Sheyn will gain experience in the three research areas: 1) development of soft tissue and cartilage biology; 2) immunology and inflammation; 3) quantitative imaging of soft tissue using magnetic resonance imaging (MRI). We will utilize formal workshops and courses and hands-on research supervised by seasoned mentors with extensive track record in these areas and mentorship to achieve those training goals. In the proposed study we will study the link between the possible mechanism of disc degeneration and the potential cell therapy. Firstly, we will investigate the developmental phenotype of novel induced pluripotent stem cell- derived notochordal cells as a potential source of cells to reverse the degeneration process and fibrosis of the disc. This aim will be conducted under mentorship of Dr. Lyons, well-established developmental and musculoskeletal biologist from UCLA and Dr. Hoyland, world expert in the notochord and IVD biology from Manchester U, UK. Secondly we will use the annular injury model of disc degeneration in pigs to study the role of pro-inflammatory and catabolic cytokines expressed by the NP cells under mentorship of Dr. Arditi, world known expert in immunology, inflammation and fibrosis., In Aim 3, the IVD degeneration will be assessed using MRI as shown in preliminary results, but also we will monitor the regeneration of the IVD using iPS-derived notochordal-like cells will be monitored under supervision of Dr. Li, world leader in MR research and imaging. Overall this study will improve our understanding of the disc degeneration and possible regeneration strategies, as well as will serve as excellent vehicle for Dr. Sheyn to strengthen his expertise in areas critical for addressing the DDD therapy and will place him in strong position to establish independent research to compete for substantial funding (R01).

项目概要/摘要 多达 80% 的成年人在一生中的某个时刻经历过背痛。之前的研究 表明 40% 的患者背痛与椎间盘 (IVD) 退变之间存在联系。尽管 经过数十年的研究，针对根本原因而不是症状的强有力的治疗方法仍处于最早阶段 发展阶段。因此，迫切需要替代治疗，例如干细胞疗法， 专注于纠正 DDD 的潜在发病机制。 Sheyn 博士的目标是发展他的学术生涯 在肌肉骨骼组织工程和干细胞治疗领域，专注于脊柱治疗。他有 在干细胞操作和基因传递、体内模型、骨组织工程方面接受过良好的培训 和分子生物学。他在该领域的出版物中建立了良好的记录，并证明了 较强的创新研究能力。拟议的培训计划旨在以博士为基础。 Sheyn 的背景并增强了他在与 IVD 治疗最相关的特定领域的专业知识。在下面 Cedars-Sinai 再生医学中心主任 Clive Svendsen 博士的领导和赞助 Sheyn博士将在研究所获得三个研究领域的经验：1）软组织和软骨的发育 生物学; 2）免疫学和炎症； 3）利用磁共振对软组织进行定量成像 成像（MRI）。我们将利用正式的研讨会和课程以及由经验丰富的人监督的实践研究 在这些领域拥有丰富记录的导师以及实现这些培训目标的指导。在 拟议的研究我们将研究椎间盘退变的可能机制和潜在的之间的联系 细胞疗法。首先，我们将研究新型诱导多能干细胞的发育表型- 衍生的脊索细胞作为逆转脊索退化过程和纤维化的潜在细胞来源 光盘。这一目标将在 Lyons 博士的指导下进行，他拥有完善的发展和 加州大学洛杉矶分校 (UCLA) 的肌肉骨骼生物学家和脊索和 IVD 生物学世界专家 Hoyland 博士 英国曼彻斯特大学。其次我们将利用猪椎间盘退变的环状损伤模型来研究其作用 在 Arditi 博士的指导下，世界各地的 NP 细胞表达促炎和分解代谢细胞因子 免疫学、炎症和纤维化领域的知名专家。在目标 3 中，将使用以下方法评估 IVD 退化 初步结果显示 MRI，但我们也将使用 iPS 衍生来监测 IVD 的再生 脊索样细胞将在核磁共振研究和成像领域的世界领导者李博士的监督下进行监测。 总的来说，这项研究将提高我们对椎间盘退变和可能的再生的理解 战略，并将成为 Sheyn 博士加强关键领域专业知识的绝佳工具 致力于解决 DDD 疗法，并将使他处于有利地位来建立独立研究 竞争大量资金（R01）。

项目成果

Electrospun, synthetic bone void filler promotes human MSC function and BMP-2 mediated spinal fusion.

• DOI: 10.1177/0885328220937999
• 发表时间: 2020-10
• 期刊: Journal of biomaterials applications
• 影响因子: 2.9
• 作者: Glaeser JD;Salehi K;Kanim LE;Ju DG;Hyuk Yang J;Behrens PH;Eberlein SA;Metzger MF;Arabi Y;Stefanovic T;Sheyn D;W Bae H
• 通讯作者: W Bae H

Single-cell atlas unveils cellular heterogeneity and novel markers in human neonatal and adult intervertebral discs.

单细胞图谱揭示了人类新生儿和成人椎间盘的细胞异质性和新标记。

• DOI: 10.1016/j.isci.2022.104504
• 发表时间: 2022-07-15
• 期刊: iScience
• 影响因子: 5.8
• 作者: Jiang W;Glaeser JD;Salehi K;Kaneda G;Mathkar P;Wagner A;Ho R;Sheyn D
• 通讯作者: Sheyn D

Assessing the Resident Progenitor Cell Population and the Vascularity of the Adult Human Meniscus.

• DOI: 10.1016/j.arthro.2020.09.021
• 发表时间: 2021-01
• 期刊: Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association
• 作者: Chahla J;Papalamprou A;Chan V;Arabi Y;Salehi K;Nelson TJ;Limpisvasti O;Mandelbaum BR;Tawackoli W;Metzger MF;Sheyn D
• 通讯作者: Sheyn D

Molecular pain markers correlate with pH-sensitive MRI signal in a pig model of disc degeneration.

• DOI: 10.1038/s41598-018-34582-6
• 发表时间: 2018-11-26
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bez M;Zhou Z;Sheyn D;Tawackoli W;Giaconi JC;Shapiro G;Ben David S;Gazit Z;Pelled G;Li D;Gazit D
• 通讯作者: Gazit D

Retention of Human iPSC-Derived or Primary Cells Following Xenotransplantation into Rat Immune-Privileged Sites.

• DOI: 10.3390/bioengineering10091049
• 发表时间: 2023-09-06
• 期刊: Bioengineering (Basel, Switzerland)