小柯机器人

近日，美国斯坦福大学Charles K. F. Chan、Michael T. Longaker等研究人员合作发现，衰老的骨骼干细胞产生一种炎症退化微环境。相关论文于2021年8月11日在线发表在《自然》杂志上。

研究人员表明，小鼠骨骼干细胞（SSC）的内在衰老改变了骨髓微环境的信号，使得骨和血谱系的分化发生偏差，导致骨骼脆弱，再生能力差。在功能上，衰老SSC的骨和软骨形成潜力下降，但产生更多的基质谱系，并表达高水平的促炎症和促吸收的细胞因子。单细胞RNA测序研究将功能丧失与老年小鼠SSC的转录组多样性减少联系起来，从而促进了骨髓微环境的转变。暴露于年轻的血液循环并没有扭转老年SSC骨软化活性的减弱，也没有改善老年小鼠的骨量或骨骼愈合参数。

相反，衰老的SSC谱系促进了造血干细胞和祖细胞的破骨活性和骨髓倾斜，这表明SSC的衰老是造血衰老的一个驱动因素。老年小鼠的骨再生缺陷只能通过在骨折处应用BMP2和CSF1拮抗剂的组合治疗来恢复到年轻水平，这重新激活了衰老的SSC，并同时消除了炎性破骨细胞的环境。这些研究结果为复杂的、多因素的骨骼老化机制提供了机理上的见解，并为恢复老年骨骼系统的活力提供了前景。

据悉，衰老和疾病期间，骨骼完整性的丧失与成骨细胞和破骨细胞对立作用的失调有关。

附：英文原文

Title: Aged skeletal stem cells generate an inflammatory degenerative niche

Author: Ambrosi, Thomas H., Marecic, Owen, McArdle, Adrian, Sinha, Rahul, Gulati, Gunsagar S., Tong, Xinming, Wang, Yuting, Steininger, Holly M., Hoover, Malachia Y., Koepke, Lauren S., Murphy, Matthew P., Sokol, Jan, Seo, Eun Young, Tevlin, Ruth, Lopez, Michael, Brewer, Rachel E., Mascharak, Shamik, Lu, Laura, Ajanaku, Oyinkansola, Conley, Stephanie D., Seita, Jun, Morri, Maurizio, Neff, Norma F., Sahoo, Debashis, Yang, Fan, Weissman, Irving L., Longaker, Michael T., Chan, Charles K. F.

Issue&Volume: 2021-08-11

Abstract: Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts1. Here we show that intrinsic ageing of skeletal stem cells (SSCs)2 in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system. An analysis of skeletal stem cells in mice reveals that bone ageing occurs at the level of local niches affecting skeletal and haematopoietic lineage output, which may influence systemic aspects of multi-organ physiological ageing.

DOI: 10.1038/s41586-021-03795-7

Source: https://www.nature.com/articles/s41586-021-03795-7

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