Potential of Hematopoietic Stem Cell-Based Therapies for Complicated Fractures

基于造血干细胞的复杂骨折疗法的潜力

• 批准号: 10045563
• 负责人: AMANDA C. LARUE
• 金额: --
• 依托单位: RALPH H JOHNSON VA 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: 2009-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045563
• 关键词: AMD3100; Affect; Animals; Antidepressive Agents; Atrophic; BMP2 gene; Blast Injuries; Blood; Bone Regeneration; Bone remodeling; Calvaria; Cell Compartmentation; Cell Therapy; Cells; Chondrocytes; Clinic; Clinical; Clone Cells; Complex; Complication; Data; Defect; Development; Devices; Disease; FDA approved; Femoral Fractures; Fracture; Fracture Healing; Goals; Healthcare; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Impaired healing; Impairment; Implant; In Vitro; Injury; Intervention; Major Depressive Disorder; Mesenchymal Stem Cells; Methods; Military Personnel; Mission; Modality; Modeling; Mus; Musculoskeletal; Operative Surgical Procedures; Orthopedics; Osteoblasts; Osteocytes; Osteogenesis; Paroxetine; Pharmacological Treatment; Population; Post-Traumatic Stress Disorders; Pre-Clinical Model; Prevalence; Publishing; Role; Selective Serotonin Reuptake Inhibitor; Sertraline; Somatomedins; Source; Survivors; Testing; Therapeutic; Time; Transgenic Mice; Translating; Trauma; Veterans; Work; base; bone; bone cell; bone healing; bone health; bone morphogenetic protein 9; clinical application; combat; combat casualty; combat veteran; combat wound; depressive symptoms; efficacy evaluation; experience; experimental study; healing; hematopoietic stem cell differentiation; high risk; in vitro testing; in vivo; injured; injury and repair; innovation; limb injury; migration; military veteran; mouse model; musculoskeletal injury; negative affect; novel; novel therapeutics; osteogenic; osteoprogenitor cell; paxil; peripheral blood; progenitor; recruit; repaired; stem; stem cell differentiation; stem cell proliferation; stem cell therapy; stem cells; transplant model

Musculoskeletal extremity injuries comprise ~50% of all combat wounds for OIF/OEF/OND Veterans. Blast injuries via improvised explosive devices account for over 75% of combat casualties, with survivors experiencing severe orthopedic injuries. These types of orthopedic injuries often result in delayed or non-union, wherein normal bone healing is impaired. Current interventions for non-union fractures, particularly atrophic non-union fractures are rarely successful. OIF/OEF/OND Veterans are also at a high risk for depressive and depressive-associated disorders including post-traumatic stress disorder (PTSD), resulting in >60% of this population being prescribed antidepressants, specifically selective serotonin reuptake inhibitors (SSRIs). While the effects of SSRIs on fracture healing are unknown, it has been shown that Sertraline (Zoloft) and Paroxetine (Paxil), first-line SSRIs for pharmacological treatment of these disorders, negatively affect bone health. Given the prevalence of complex orthopedic injuries, the long-term complications from these injuries, and the commonness of SSRI use in the OIF/OEF/OND Veteran population, there is a need for new therapies (e.g., cell-based therapies) that may overcome current clinical limitations for complicated fractures. Our studies using a unique clonal cell transplantation model in conjunction with murine fracture models has identified the hematopoietic stem cell (HSC) as a novel progenitor for osteoblasts, osteocytes, and chondrocytes during fracture repair. Recent studies show HSC-derived osteoprogenitors directly give rise to bone in vivo. These findings are paradigm shifting in that most studies focus on the use of mesenchymal stem cells (MSCs) for musculoskeletal injury repair and suggest a benefit of HSC-based therapies for complicated fracture. Building on our previous MERIT studies, which demonstrated a role for bone morphogenetic protein-2 (BMP-2), BMP-9, and insulin-like growth factor (IGF-2) in promoting osteogenesis from the HSC, we have now shown a combination of IGF-2+BMP-9 results in enhanced osteoinduction from HSC-osteogenic precursors. We have also identified HSC-derived circulating osteogenic progenitors (COPs) that increase in blood during normal fracture repair and are mobilized with AMD3100 delivery, suggesting a potential therapeutic modality. Our preliminary data also demonstrate that SSRI administration in vivo leads to impaired bone healing, results in altered osteogenic profiles during healing, and inhibits osteoinduction from HSC-progenitors in vitro. We hypothesize that HSC-derived osteo-chondrogenic progenitor cells may be targeted to enhance repair of complicated fractures. Our goals are to examine the ability of HSC-derived osteo-chondrogenic progenitors (compared to MSCs) to serve as a therapeutic modality during complicated non-union fractures and fractures during SSRI administration, uncover the mechanisms by which these cells may have a beneficial effect, and elucidate the effects of SSRIs on this unique population of progenitor cells. Specific Aims are to determine 1) if modulation of HSC-derived osteo-chondrogenic precursors in vivo promotes healing in a model of atrophic non-union and 2) if SSRIs impair fracture healing via inhibition of HSC-derived osteogenic precursors. These studies are significant in that they challenge existing dogma by suggesting a novel HSC origin for bone cells and innovative in that they will determine the potential of exploiting HSCs to enhance healing in cases of complicated fracture. Findings from this study are easily translated to clinic (HSC mobilization is FDA approved for other applications) and have the potential to directly impact Veteran Health Care. Understanding how SSRIs affect bone healing and specific stem cell compartments may have tremendous clinical impact given the large number of injured Veterans prescribed SSRIs. This work will have far-reaching benefit for military personnel and Veterans at high risk for complicated fracture, specifically those of OIF/OEF/OND being treated for clinical depression and/or PTSD using an SSRI, and thus, is highly relevant to the VA Mission.

OIF/OEF/OND 退伍军人的所有战斗伤口中，肌肉骨骼四肢损伤约占 50%。爆炸 简易爆炸装置造成的伤害占战斗伤亡人数的 75% 以上，幸存者 遭受严重的骨科损伤。这些类型的骨科损伤通常会导致延迟愈合或不愈合， 其中正常的骨愈合受到损害。目前针对不愈合骨折（尤其是萎缩性骨折）的干预措施 骨折不愈合很少成功。 OIF/OEF/OND 退伍军人也面临着抑郁和抑郁症的高风险。 抑郁相关疾病，包括创伤后应激障碍 (PTSD)，导致超过 60% 正在服用抗抑郁药的人群，特别是选择性血清素再摄取抑制剂（SSRI）。尽管 SSRIs 对骨折愈合的影响尚不清楚，已证明舍曲林（左洛复）和帕罗西汀 (Paxil)，用于药物治疗这些疾病的一线 SSRIs，会对骨骼健康产生负面影响。给定 复杂骨科损伤的患病率、这些损伤的长期并发症以及 鉴于 SSRI 在 OIF/OEF/OND 退伍军人群体中使用的普遍性，需要新的疗法（例如， 基于细胞的疗法）可以克服当前复杂骨折的临床限制。 我们的研究使用独特的克隆细胞移植模型与小鼠骨折模型相结合 确定造血干细胞（HSC）是成骨细胞、骨细胞和成骨细胞的新型祖细胞 骨折修复过程中的软骨细胞。最近的研究表明 HSC 衍生的骨祖细胞直接产生 体内的骨头。这些发现是范式转变，因为大多数研究都集中在间充质干细胞的使用上 细胞（MSC）用于肌肉骨骼损伤修复，并表明基于 HSC 的疗法对于复杂的治疗有好处 断裂。基于我们之前的 MERIT 研究，该研究证明了骨形态发生蛋白 2 的作用 (BMP-2)、BMP-9 和胰岛素样生长因子 (IGF-2) 在促进 HSC 成骨方面的作用，我们现在已经 显示 IGF-2+BMP-9 的组合可增强 HSC 成骨前体的骨诱导作用。 我们还鉴定了 HSC 衍生的循环成骨祖细胞 (COP)，其在血液中增加 正常的骨折修复，并通过 AMD3100 输送进行动员，这表明了一种潜在的治疗方式。 我们的初步数据还表明，体内施用 SSRI 会导致骨愈合受损，结果 在愈合过程中改变成骨特征，并在体外抑制 HSC 祖细胞的骨诱导。 我们假设 HSC 衍生的骨软骨祖细胞可能有针对性地增强修复 复杂骨折。我们的目标是检查 HSC 衍生的骨软骨祖细胞的能力 （与间充质干细胞相比）作为复杂骨折不愈合和骨折的治疗方式 在 SSRI 给药期间，揭示这些细胞可能产生有益作用的机制，以及 阐明 SSRIs 对这种独特的祖细胞群的影响。具体目标是确定 1) 如果体内调节 HSC 衍生的骨软骨前体可以促进萎缩模型的愈合 骨不连；2) SSRIs 是否通过抑制 HSC 衍生的成骨前体细胞而损害骨折愈合。 这些研究的意义重大，因为它们通过提出新的 HSC 起源来挑战现有的教条。 骨细胞的创新之处在于它们将确定利用造血干细胞增强愈合的潜力 复杂性骨折病例。这项研究的结果很容易转化为临床（HSC 动员是 FDA 批准用于其他应用）并有可能直接影响退伍军人医疗保健。理解 SSRIs 如何影响骨愈合和特定干细胞区室可能产生巨大的临床影响 鉴于大量受伤退伍军人服用了 SSRIs。这项工作将产生深远的效益 复杂性骨折高风险的军事人员和退伍军人，特别是 OIF/OEF/OND 的人员 使用 SSRI 治疗临床抑郁症和/或 PTSD，因此与 VA 使命高度相关。