Hypertrophic chondrocytes serve as a reservoir for marrow-associated skeletal stem and progenitor cells, osteoblasts, and adipocytes during skeletal development.
Hypertrophic chondrocytes serve as a reservoir for marrow-associated skeletal stem and progenitor cells, osteoblasts, and adipocytes during skeletal development.
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DOI：
10.7554/elife.76932
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发表时间：
2022-02-18
期刊：
影响因子：
7.7
通讯作者：
Hilton MJ
中科院分区：
文献类型：
--
作者：
Long JT;Leinroth A;Liao Y;Ren Y;Mirando AJ;Nguyen T;Guo W;Sharma D;Rouse D;Wu C;Cheah KSE;Karner CM;Hilton MJ
肥大的软骨细胞在骨骼发育过程中形成成骨细胞；然而，这些非有丝分裂细胞如何完成这一转变的过程尚不清楚。先前的研究也表明，骨骼干细胞和祖细胞(SSPC)定位于周围的骨膜，是骨骼发育过程中骨髓相关SSPC、成骨细胞、骨细胞和脂肪细胞的主要来源。为了进一步了解肥大的软骨细胞对成骨细胞或其他骨髓相关细胞的细胞转化过程，我们利用了可诱导的和结构性的肥大软骨细胞谱系追踪和报告小鼠模型(Col10a1CreERT2；Rosa26fs-tdTomato和Col10a1Cre；Rosa26fs-tdTomato)，并结合PDGFRaH2B-GFP转基因系、单细胞RNA测序、批量RNA测序、免疫荧光染色和细胞移植实验。我们的数据表明，肥大的软骨细胞经历了一个去分化的过程，以产生骨髓相关的SSPC，在骨骼发育过程中作为成骨细胞的主要来源。这些肥大的软骨细胞来源的SSPC在骨骼发育过程中致力于CXCL12丰富的网状(CAR)细胞表型，并显示出独特的招募血管形成和促进骨髓建立的能力，同时也有助于成脂血统。
Hypertrophic chondrocytes give rise to osteoblasts during skeletal development; however, the process by which these non-mitotic cells make this transition is not well understood. Prior studies have also suggested that skeletal stem and progenitor cells (SSPCs) localize to the surrounding periosteum and serve as a major source of marrow-associated SSPCs, osteoblasts, osteocytes, and adipocytes during skeletal development. To further understand the cell transition process by which hypertrophic chondrocytes contribute to osteoblasts or other marrow associated cells, we utilized inducible and constitutive hypertrophic chondrocyte lineage tracing and reporter mouse models (Col10a1CreERT2; Rosa26fs-tdTomato and Col10a1Cre; Rosa26fs-tdTomato) in combination with a PDGFRaH2B-GFP transgenic line, single-cell RNA-sequencing, bulk RNA-sequencing, immunofluorescence staining, and cell transplantation assays. Our data demonstrate that hypertrophic chondrocytes undergo a process of dedifferentiation to generate marrow-associated SSPCs that serve as a primary source of osteoblasts during skeletal development. These hypertrophic chondrocyte-derived SSPCs commit to a CXCL12-abundant reticular (CAR) cell phenotype during skeletal development and demonstrate unique abilities to recruit vasculature and promote bone marrow establishment, while also contributing to the adipogenic lineage.