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: 8294322
• 负责人: Wei Yao
• 金额: $ 27.72万
• 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/8294322
• 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

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. PUBLIC HEALTH RELEVANCE: Aged individuals have reduced numbers of mesenchymal stem cells (MSCs) in the bone marrow which leads to impairment of bone forming ability and subsequent bone loss (osteoporosis). MSCs are the cells that can give rise to the osteoblasts, the cells that make bone. Giving extra MSCs to patients with severe osteoporosis or delayed fracture healing would be a good therapeutic option. However, this approach was not successful due to the transplanted MSCs can not readily go to bone. Our research group has developed a novel method to guide the transplanted MSCs to bone by creating a compound with high affinity to both to the MSCs and bone. The goal of this project is to test whether we can build new bone in preclinical studies of bone loss using our lead compound, LLP2A-Ale alone, or in the combination of MSCs transplantation, to increase bone formation and if our approach has the potential to make more bones and stronger bones.

描述（由申请人提供）：衰老会减少骨髓中间充质干细胞（MSC）的数量，从而导致成骨受损和随后的骨质流失（骨质疏松症）。之前使用系统性间充质干细胞移植的尝试未能使骨再生，因为移植的间充质干细胞无法归巢于骨。如果间充质干细胞移植可以定向到骨骼并诱导分化为成骨细胞，那么它可能是治疗骨质流失的一种治疗选择。我们的研究小组开发了一种新方法，通过创建一种对 MSC 上的 ?4?1 整合素（一种合成的拟肽配体，LLP2A）和骨骼（阿仑膦酸钠）具有高亲和力的化合物，将移植的 MSC 定向到骨骼。由此产生的缀合物 LLP2A-Ale 显着增加了移植的 MSC 向骨的归巢，并在异种移植模型中经历了成骨细胞分化。 LLP2A-Ale 还增加了年轻免疫活性小鼠的骨形成和骨量。我们已经证明，间充质干细胞附着在骨上，并在“定向”到骨表面时进行成骨分化。尽管 LLP2A-Ale 对幼年动物有效，但该化合物未能显着增强老年动物的骨形成，除非与全身性 MSC 移植联合使用。此外，缺乏疾病模型的数据。因此，我们建议测试 LLP2A-Ale 在骨质疏松和骨折愈合动物模型中指导移植的 MSC 增强骨形成的有效性。我们假设，在治疗因衰老、激素缺乏或其他疾病引起的严重骨质疏松症时，LLP2A-Ale 会将移植的 MSC 引导至骨表面并促进新骨形成。为了检验这一假设，我们提出以下两个目标。 1. 确定 LLP2A-Ale 或与 MSC 移植组合在骨质疏松动物模型中增强骨形成的功效。 2. 确定 LLP2A-Ale 单独使用或与 MSC 联合使用是否会增加 MSC 植入并加速骨折愈合。该项目的目标是测试我们是否可以通过使用 LLP2A-Ale 将 MSC 移植到骨骼中来构建新骨作为骨质疏松症的新型治疗方法。我们的初步数据表明，LLP2A-Ale 实际上可以将移植的人类 MSC 引导至骨骼并进行成骨细胞分化。这对于使用 MSC 治疗骨质疏松症非常重要，因为主要障碍是 MSC 归巢效率低下。我们的新方法对于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疗等药物引起的继发性骨质疏松症患者有效。我们的先导化合物 LLP2-Ale 在临床前研究中经过彻底测试后，具有进入临床实践的巨大潜力。 公共卫生相关性：老年人骨髓中间充质干细胞 (MSC) 数量减少，导致骨形成能力受损和随后的骨质流失（骨质疏松症）。间充质干细胞是可以产生成骨细胞（形成骨骼的细胞）的细胞。为患有严重骨质疏松症或骨折延迟愈合的患者提供额外的间充质干细胞将是一个很好的治疗选择。然而，由于移植的间充质干细胞不能轻易进入骨骼，这种方法并不成功。我们的研究小组开发了一种新方法，通过创造一种对间充质干细胞和骨骼都具有高亲和力的化合物来引导移植的间充质干细胞到达骨骼。该项目的目标是测试我们是否可以在骨质流失的临床前研究中使用我们的先导化合物 LLP2A-Ale 单独或与 MSC 移植相结合来构建新骨，以增加骨形成，以及我们的方法是否有潜力使骨骼更多、更强壮。