Inflamm-aging of osteoprogenitor cells: A therapeutic target for improved bone healing

项目总结 成人身体的维持、重塑和修复是由多能干细胞介导的，这些干细胞能产生 构成它们所在组织的各种细胞类型。在衰老过程中，体内平衡会下降。 再生能力导致重要器官结构和功能的进行性退化。在……里面 特别是，肌肉骨骼退化在老年人中很常见，并会导致骨折风险增加和 骨折修复效率降低，严重降低了生活质量。我们之前的研究表明， 与年龄相关的慢性低度炎症增加是骨干和骨祖细胞的主要原因。 细胞(SSPC)功能障碍。因此，我们假设，减少促炎信号和增强抗炎作用 炎症活动将挽救老年人SSPC的数量和成骨功能。为了调查此事， 我们将首先精确定义调节SSPC炎症反应的分子机制， 以及抗炎因子在炎症消退中的作用。我们将确定这些 相反的促炎和抗炎信号之间的相互作用和机制受到衰老的影响。 这些实验将对导致骨骼退化的因素产生洞察力，并确定 改善老年患者骨骼健康和骨折修复的治疗目标。我们强势的预赛 实验还发现了两个与SSPC在老化过程中恶化有关的主要嫌疑人。我们将表演 SSPC功能获得和丧失实验以阐明其在干细胞控制中的特定作用 自我更新和差异化。因为操纵这些因子可以影响细胞外炎症。 我们将使用单细胞RNA测序来确定它们在SSPC中的细胞固有功能以及它们的 对当地生态位内确定的人口的影响。最后，我们将操作候选表达式 老年动物受伤后评估其拯救干细胞再生能力和 促进骨骼愈合。

PROJECT SUMMARY Maintenance, remodeling, and repair of the adult body is mediated by multipotent stem cells that give rise to a variety of cell types that comprise the tissue in which they reside. During aging, there is a decline in homeostatic and regenerative capacity leading to progressive degeneration of the structure and function of vital organs. In particular, musculoskeletal degeneration is common in the elderly and leads to increased fracture risk and reduced efficiency of fracture repair that drastically decreases quality of life. Our previous studies showed that an age-associated increase in chronic, low-grade inflammation is the main cause of skeletal stem and progenitor cell (SSPCs) dysfunction. Thus, we hypothesize that reducing pro-inflammatory signals and enhancing anti- inflammatory activity will rescue SSPC number and osteogenic function in aged individuals. To investigate this, we will first precisely define the molecular mechanisms regulating the inflammatory response in SSPCs, and the role of anti-inflammatory factors in the resolution of inflammation. We will determine how these mechanisms and the interaction between opposing pro- and anti- inflammatory signals is affected by aging. These experiments will generate insights into the elements driving bone degeneration and identify therapeutic targets to improve bone health and fracture repair in elderly patients. Our strong preliminary experiments also identified two prime suspects involved in SSPC deterioration during aging. We will perform gain and loss of function experiments in SSPCs to elucidate their specific role in the control of stem cell self-renewal and differentiation. As manipulation of these factors can affect the extracellular inflammatory milieu, we will use single-cell RNA-sequencing to determine their cell-intrinsic function in SSPCs and also their influence on defined populations within the local niche. Finally, we will manipulate candidate expression following injury in aged animals to assess their ability to rescue stem cell regenerative capacity and improve bone healing.