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Altered gene expression in multiple key pathways in MSCs from people with osteoporosis compared to people who do not have osteoporosis

ABSTRACT: Osteoporosis is caused by imbalanced bone remodelling homeostasis and is highly prevalent in post-menopausal women. The impact of osteoporosis on mesenchymal stromal cells (MSCs) is a key area of research as they are the progenitors of osteoblasts and are therefore critical to bone homeostasis. TBioinformatic analysis of transcriptional profiling data revealed specific misregulation of genes involved in the processing and trafficking of cellular components, as well as downregulation of Neo1 which has an important role in controlling cell fate choice. These data indicate that the therapeutic targeting of bone marrow MSCs to increase their numbers, to support the appropriate processing of cellular contents, or to redirect cell fate choice may provide new methods for the treatment of osteoporosis, thereby reducing fracture-associated morbidity and improving quality of life for the 200 million people living with osteoporosis globally.

ORGANISM(S): Homo sapiens

PROVIDER: GSE189524 | GEO | 2024/04/09

REPOSITORIES: GEO

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Project description:The efficient clearance of dead and dying cells, also known as efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs in the BMME and on their function. To investigate this, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including osteoporosis in aging.

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Altered gene expression in multiple key pathways in MSCs from people with osteoporosis compared to people who do not have osteoporosis

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