Stem cells from the intervertebral disc: do they vary in degeneration?

来自椎间盘的干细胞：它们的退化程度不同吗？

• 批准号: 7895776
• 负责人: Zulma Gazit
• 金额: $ 8.13万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895776
• 关键词: Adult; Affect; Alginates; Area; Binding; Biological Assay; Bone Tissue; Bromodeoxyuridine; Cardiomyopathies; Cartilage; Cell Nucleus; Cell Separation; Cells; Chondrogenesis; Chronic low back pain; Clinical; Collagen; Complex; Data; Degenerative polyarthritis; Development; Dyes; Extracellular Matrix; Family suidae; Fracture; Future; Gene Expression; Gene Proteins; Goals; Growth; Health; Homeostasis; Hypoxia; In Vitro; Injury; Inorganic Sulfates; Intervertebral disc structure; Lead; Life; Measures; Mesenchymal Differentiation; Methylene blue; Myocardium; Natural regeneration; Osteogenesis; Osteoporosis; Pathology; Pathway interactions; Pattern; Pilot Projects; Play; Process; Research; Role; Route; SOX9 protein; Source; Staging; Stem cells; Surface Antigens; Symptoms; Testing; Tissues; Unspecified or Sulfate Ion Sulfates; adult stem cell; aggrecan; cost; disc regeneration; glucosaminoglycans; intervertebral disk degeneration; lipid biosynthesis; multidisciplinary; nucleus pulposus; programs; public health relevance; small molecule

DESCRIPTION (provided by applicant): Project Summary: Stem Cells from the Intervertebral Disc: Do They Vary in Degeneration? Degenerative disc disease and its associated chronic lower back pain is a major U.S. health problem with estimated costs of up to $50 billion yearly. Despite decades of research, a fundamental, multidisciplinary mechanistic understanding of disc degeneration is lacking and, consequently, robust clinical therapies which target the underlying causes rather than the symptoms, are still in the earliest stages of development. In the proposed research program, we focus on the comparison between stem cells (SCs) residing in the nucleus pulposus from healthy and degenerated intervertebral discs. Adults SCs have been known to regulate bone tissue homeostasis and to play an important role in regeneration following injury (i.e. fracture). It was speculated that SCs maintain tissue homeostasis also in tissues with limited regeneration capacity, such as cartilage and the myocardium. Yet it has been shown that during certain pathologies, such as osteoarthritis, osteoporosis and cardiomyopathies, abnormal growth pattern, and changes in differentiation of resident SCs are observed. These changes could attribute to the loss of homeostasis and diminished regeneration process. We have recently shown that SCs do exist in the IVD, even in its degenerated state. There is also some evidence indicating that SCs from other adult tissues might give rise to differentiated nucleus pulposus (NP)-like cells that synthesize and secrete the NP extracellular matrix (ECM). In the proposed study we ask whether the process of disc degeneration affects NP- derived SCs? Our overarching hypothesis is that SCs residing in the degenerated nucleus pulposus demonstrate a change in their number and/or differentiation profile compared to SCs in healthy discs. In order to validate our hypothesis we will pursue the following specific aims: Aim 1. To evaluate the number, proliferation and differentiation potential of SCs from the NP as a function of disc degeneration. Aim 2 To evaluate the differentiation potential of SCs derived from degenerated discs to NP-like cells. The results of this study could provide evidence to a potential role of resident SCs in the process of disc degeneration. Specifically, our findings could be the first step in understanding why resident SCs do not reverse the degenerative process within the disc. Furthermore, the data provided by this study could indicate the route, which future therapies for disc degeneration should take. If indeed NP SCs are found in very low numbers in the disc, exogenous introduction of SCs from other sources could be beneficial for disc regeneration. However, if NP-SCs do maintain some differentiation potential than they might be induced to regenerate the disc by certain genes, proteins or small molecules. PUBLIC HEALTH RELEVANCE: Project Narrative: Stem Cells from the Intervertebral Disc: Do They Vary in Degeneration The proposed study aims to investigate stem cells residing in the nucleus pulposus. It is our hypothesis that stem cells residing in the degenerated nucleus pulposus demonstrate a change in their number and/or differentiation profile compared to SCs in healthy discs.

描述（由申请人提供）： 项目摘要：来自椎间盘的干细胞：它们的退化情况是否有所不同？退行性椎间盘疾病及其相关的慢性腰痛是美国的一个主要健康问题，估计每年造成的损失高达 500 亿美元。尽管进行了数十年的研究，但仍缺乏对椎间盘退变的基本、多学科机制的理解，因此，针对根本原因而不是症状的强有力的临床治疗仍处于发展的最初阶段。在拟议的研究计划中，我们重点关注健康和退化椎间盘髓核中的干细胞（SC）之间的比较。众所周知，成人 SC 可以调节骨组织稳态，并在损伤（即骨折）后的再生中发挥重要作用。据推测，SCs 在再生能力有限的组织中也能维持组织稳态，例如软骨和心肌。然而，已经表明，在某些病理过程中，例如骨关节炎、骨质疏松症和心肌病，可以观察到常驻 SC 的异常生长模式和分化变化。这些变化可能归因于体内平衡的丧失和再生过程的减少。我们最近表明，SC 确实存在于 IVD 中，即使处于退化状态。还有一些证据表明，来自其他成体组织的 SC 可能会产生分化的髓核 (NP) 样细胞，合成和分泌 NP 细胞外基质 (ECM)。在拟议的研究中，我们询问椎间盘退变过程是否会影响 NP 衍生的 SC？我们的总体假设是，与健康椎间盘中的 SC 相比，退变髓核中的 SC 表现出数量和/或分化特征的变化。为了验证我们的假设，我们将追求以下具体目标： 目标 1. 评估来自 NP 的 SC 的数量、增殖和分化潜力，作为椎间盘退变的函数。目的 2 评估退变椎间盘来源的 SC 向 NP 样细胞的分化潜力。这项研究的结果可以为驻留 SC 在椎间盘退变过程中的潜在作用提供证据。具体来说，我们的发现可能是理解为什么驻留 SC 不能逆转椎间盘退变过程的第一步。此外，这项研究提供的数据可以表明未来椎间盘退变治疗应采取的路线。如果确实在椎间盘中发现 NP SC 的数量非常低，那么从其他来源外源引入 SC 可能有利于椎间盘再生。然而，如果 NP-SC 确实保持一定的分化潜力，那么它们可能会被某些基因、蛋白质或小分子诱导再生椎间盘。 公共卫生相关性： 项目叙述：来自椎间盘的干细胞：它们在退化方面是否有所不同拟议的研究旨在研究存在于髓核中的干细胞。我们的假设是，与健康椎间盘中的 SC 相比，退变髓核中的干细胞表现出数量和/或分化特征的变化。

项目成果

Matrix stiffness determines the fate of nucleus pulposus-derived stem cells.

基质硬度决定髓核干细胞的命运。

• DOI: 10.1016/j.biomaterials.2015.01.021
• 发表时间: 2015-05-01
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Yosi Navaro;Nadav Bleich;L. Hazanov;I. Mironi‐Harpaz;Yonatan Shachaf;S. Garty;Y. Smith;G. Pelled;D. Gazit;D. Seliktar;Z. Gazit
• 通讯作者: Z. Gazit

Nucleus pulposus degeneration alters properties of resident progenitor cells.

髓核变性改变了祖细胞的特性。

• DOI: 10.1016/j.spinee.2013.02.065
• 发表时间: 2013-07
• 期刊: The spine journal : official journal of the North American Spine Society
• 影响因子: 4.5
• 作者: Mizrahi, Olga;Sheyn, Dmitriy;Tawackoli, Wafa;Ben-David, Shiran;Su, Susan;Li, Ning;Oh, Anthony;Bae, Hyun;Gazit, Dan;Gazit, Zulma
• 通讯作者: Gazit, Zulma