Directing mesenchymal stem cells to bone to augment bone formation

将间充质干细胞引导至骨骼以增强骨形成

• 批准号: 8721344
• 负责人: Wei Yao
• 金额: $ 27.17万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721344
• 关键词: 3-Dimensional; Affect; Affinity; Aging; Alendronate; Anabolic Agents; Animal Model; Animals; Architecture; Biochemical; Bone Growth; Bone Marrow; Bone Surface; Cells; Chondrogenesis; Data; Disease; Disease model; Effectiveness; Elderly; Engraftment; Estrogens; Fracture; Fracture Healing; Glucocorticoids; Goals; Growth Factor; Home environment; Homing; Human; Immune; Impairment; Individual; Integrins; Lead; Ligands; Measures; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; Modeling; Mus; Natural regeneration; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Process; Research; Serum; Site; Surface; Testing; Therapeutic; Time; Transplantation; Trauma; Xenograft procedure; aged; base; bone; bone loss; bone mass; bone strength; bone turnover; chemotherapy; clinical practice; hormone deficiency; juvenile animal; novel; novel strategies; osteoblast differentiation; osteogenic; parathyroid hormone (1-34); peptidomimetics; preclinical study; prevent; 3-Dimensional; Affect; Affinity; Aging; Alendronate; Anabolic Agents; Animal Model; Animals; Architecture; Biochemical; Bone Growth; Bone Marrow; Bone Surface; Cells; Chondrogenesis; Data; Disease; Disease model; Effectiveness; Elderly; Engraftment; Estrogens; Fracture; Fracture Healing; Glucocorticoids; Goals; Growth Factor; Home environment; Homing; Human; Immune; Impairment; Individual; Integrins; Lead; Ligands; Measures; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; Modeling; Mus; Natural regeneration; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Process; Research; Serum; Site; Surface; Testing; Therapeutic; Time; Transplantation; Trauma; Xenograft procedure; aged; base; bone; bone loss; bone mass; bone strength; bone turnover; chemotherapy; clinical practice; hormone deficiency; juvenile animal; novel; novel strategies; osteoblast differentiation; osteogenic; parathyroid hormone (1-34); peptidomimetics; preclinical study; prevent

DESCRIPTION (provided by applicant): Aging reduces the number of mesenchymal stem cells (MSCs) in the bone marrow which leads to impairment of osteogenesis and subsequent bone loss (osteoporosis). Previous attempts to use systematic MSC transplantation have failed to regenerate bone due to inability of the transplanted MSCs to home to bone. MSCs transplantation may be a therapeutic option to treat bone loss if the cells could be directed to bone and induced to differentiate into osteoblasts. Our research group has developed a novel method to direct transplanted MSCs to bone by creating a compound with high affinity to both the ?4?1 integrin on MSCs (a synthetic peptidomimetic ligand, LLP2A) and bone (alendronate). The resulting conjugate, LLP2A-Ale, significantly increased homing of the transplanted MSCs to bone and underwent osteoblast differentiation in a xenotransplantation model. LLP2A-Ale also increased bone formation and bone mass in young immune competent mice. We have shown that MSCs attach to bone and undergo osteogenic differentiation when they are "directed" to the bone surface. Although LLP2A-Ale is effective in young animals, the compound failed to significantly augment bone formation in aged animals unless it was used in combination with systemic MSC transplantation. Moreover, data on disease model is lacking. Therefore, we propose testing the effectiveness of LLP2A-Ale in directing the transplanted MSCs in augmenting bone formation in animal models of osteoporosis and fracture healing. We hypothesize that LLP2A-Ale will direct the transplanted MSCs to the bone surfaces and facilitate new bone formation in the treatments of severe osteoporosis caused by aging, hormone deficiency or other disorders. To test this hypothesis, we propose the following two aims. 1. To determine the efficacy of LLP2A-Ale, or in the combination with MSC transplantation, in the augmentation of bone formation in animal models of osteoporosis. 2. To determine if LLP2A-Ale alone or in combination with MSCs increases MSC engraftment and accelerates fracture healing. The goal of this project is to test whether we can build new bone as a novel treatment for osteoporosis by using LLP2A-Ale to direct transplanted MSCs to the bone. Our preliminary data suggests that LLP2A-Ale can in fact direct transplanted human MSCs to bone and undergo osteoblast differentiation. This is of enormous importance for using MSCs in the treatment of osteoporosis since the major roadblock has been inefficient homing of MSCs to bone. Our novel approach would be effective in patients with primary osteoporosis induced by estrogen deficiency or advanced aging, and in those with secondary osteoporosis due to medications such as glucocorticoids or chemotherapy. Our lead compound, LLP2-Ale, once tested thoroughly in preclinical studies, has great potential to be taken into clinical practice.

描述（由申请人提供）：老化减少了骨髓中间充质干细胞（MSC）的数量，从而导致成骨的损害和随后的骨质流失（骨质疏松症）。以前使用系统的MSC移植的尝试由于无法移植的MSC到骨骼的家园而无法再生骨骼。如果可以将细胞定向到骨骼并诱导分化为成骨细胞，则MSC的移植可能是治疗骨质流失的治疗选择。我们的研究小组开发了一种新的方法，可以通过在MSC（合成肽型配体，LLP2A）和骨（Alendronate）上产生高亲和力将移植的MSC引导至骨骼。在异种移植模型中，所得共轭的LLP2A-ale显着增加了移植的MSC的归位为骨骼并进行了成骨细胞分化。 LLP2A-ale还增加了年轻免疫胜任小鼠的骨形成和骨量。我们已经表明，当MSC被“定向”到骨表面时，它们附着在骨骼上，并经历成骨分化。尽管LLP2A-ALE在幼小动物中有效，但该化合物无法显着增加老年动物的骨形成，除非它与全身MSC移植结合使用。此外，缺乏疾病模型的数据。因此，我们提出测试LLP2A-ale在指导移植的MSC在骨质疏松和骨折愈合的动物模型中增加骨形成的有效性。我们假设LLP2A-ALE将把移植的MSC引导到骨表面，并促进由衰老，激素缺乏或其他疾病引起的严重骨质疏松症治疗的新骨形成。为了检验这一假设，我们提出了以下两个目标。 1。确定LLP2A-ALE的功效，或与MSC移植的结合，在骨质疏松动物模型中增强骨形成的功效。 2。确定LLP2A-ale是单独的还是与MSC结合的，会增加MSC的植入并加速断裂愈合。该项目的目的是测试我们是否可以通过使用LLP2A-ALE将移植的MSC引导到骨骼的骨质疏松症作为新骨头。我们的初步数据表明，LLP2A-ALE实际上可以将人类MSC直接直接移植到骨骼上并经历成骨细胞分化。这对于使用MSC治疗骨质疏松症非常重要，因为主要的障碍是MSC效率低下的骨骼。我们的新方法可有效，可对雌激素缺乏或晚期衰老引起的原发性骨质疏松症患者以及由于糖皮质激素或化学疗法等药物而引起的继发性骨质疏松症的患者。我们的铅化合物LLP2-ale曾经在临床前研究中进行了彻底的测试，具有巨大的潜力。