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Examining Skeletal Stem Cell Diversity and its Role in Intervertebral Disc Regeneration

检查骨骼干细胞多样性及其在椎间盘再生中的作用

基本信息

批准号：
10723101
负责人：
Malachia Hoover
金额：
$ 3.62万
依托单位：
STANFORD 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：
2022-08-16 至 2024-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10723101
关键词：
3-Dimensional Acute Adipose tissue Affect Age-Related Osteoporosis Animals Biological Assay Biomedical Engineering Biomimetics Bone Marrow Bone Morphogenetic Proteins Cartilage Cell surface Cells Chondrogenesis Connective Tissue Cues Data Degenerative polyarthritis Deterioration Development Embryo Evaluation FGF2 gene Femur Fibrocartilages Flow Cytometry Foundations Gene Expression Profiling Genetic Variation Growth Factor Head Hematopoiesis Homeobox Genes Human Hyaline Cartilage In Vitro Injections Injury Intervertebral disc structure Joints Knowledge Limb structure Marrow Medicine Methods Mus Musculoskeletal Diseases Natural regeneration Nature Operative Surgical Procedures Opioid Osteocytes Osteogenesis Output Pathway interactions Play Production Progressive Disease Property Recombinant Proteins Recombinants Regulation Rejuvenation Reporting Repression Research Role SHH gene Signal Transduction Site Specific qualifier value Specimen Spinal Fusion Steroids Structure Surgical Models Tail Techniques Testing Tissues Transplantation Vascular Endothelial Growth Factors Vertebral column barrier to testing bone cartilage regeneration cell type chronic back pain clinical translation combat disc regeneration effective therapy experimental study genetic signature in vivo innovation intervertebral disk degeneration lentivirally transduced mesenchymal stromal cell minimally invasive morphogens mouse model novel osteogenic pre-clinical prevent progenitor prospective reduce symptoms repaired scaffold self-renewal skeletal skeletal stem cell skeletal tissue standard care stem cell based approach stem cell expansion stem cell fate stem cell therapy stem cells targeted treatment

项目摘要

Project Summary/Abstract. The intervertebral disc (IVD) is a highly specialized, fibrocartilaginous structure that deteriorates at a rate faster than any other connective tissue in the body. This condition is commonly referred to as IVD degeneration and a critical challenge for IVD repair is the development of effective treatments that reverses the fibrocartilage damage. Due to their cell intrinsic properties of self-renewal and differentiation, the utilization of tissue resident stem cells holds promise as a stem cell-based approach to combat IVD degeneration. Our lab was the first to identify, isolate and functionally characterize bona fide skeletal stem cells (SSCs) and their committed downstream progenitors that give rise strictly to bone, cartilage, and marrow stroma in mice and humans32,33. SSCs are distinct from mesenchymal stromal cells which represent highly heterogenous mixtures of cell types57. We’ve since have leveraged our knowledge of SSCs to understand degenerative skeletal conditions including osteoarthritis, non-unions and age-related osteoporosis46,58,59. More recently, we used our isolation methods to discover tissue resident SSCs within mouse and human IVDs. In this proposal, the overarching objective is to identify the intrinsic cues that dictate SSC fate into IVD tissue as well as examine the extrinsic cues that may guide IVD regeneration using a novel microfracture surgical model in the mouse caudal IVD. Our preliminary data suggests that IVD SSCs are distinctly more chondrogenic than femur SSCs in their differentiation capacity both in vitro and in vivo. Additionally, we found that mouse IVD SSCs exclusively express HOXA4 and their skeletal fate decisions can be dictated by the addition of morphogens FGF2, SHH and WNT3A in vitro. We also found that acute microfracture injury of caudal IVDs in the mouse tail does not amplify resident IVD SSCs and transplantation of IVD SSCs into microfractured IVD fail to generate fibrocartilage, thus suggesting they may require the guidance of additional factors for cartilage differentiation in vivo. In this proposal, our overall hypothesis is that HOXA4 is an intrinsic regulator, while FGF2 is an extrinsic regulator of IVD tissue fate, and that modulating these pathways in IVD SSCs can be used as a potential stem cell-targeting therapy for combating IVD degeneration. In Aim 1, we will address this hypothesis by modulating HOXA4 expression in IVD and femur (control) SSCs via lentiviral transduction and subsequently perform in vitro and in vivo differentiation assays to assess their cartilagenic IVD output. In Aim 2, we will test if the injection of morphogens FGF2, SHH and WNT3A can change the fate decision of microfractured resident SSCs to regenerate damaged IVD tissue in vivo. Ultimately, this set of basic and pre-clinical proposed experiments will further define the concept the SSC diversity and set the foundation for the clinical translation of stem cell-based therapies for preventing and reversing IVD-related musculoskeletal diseases.

项目总结/抽象。