Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
Cell Death Dis. 2023 Jul 14;14(7):428. doi: 10.1038/s41419-023-05931-9.
The efficient clearance of dead and dying cells, 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 and on their function. To investigate, 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 bone marrow remodeling and bone loss in the setting of aging, cancer and other diseases.
细胞的有效清除对于维持组织稳态至关重要。在骨髓微环境（BMME）中，这一功能主要由专业的骨髓巨噬细胞来完成，但最近的研究表明，间充质基质细胞（MSCs）在 BMME 中作为非专业吞噬细胞发挥作用。然而，关于吞噬作用对 MSCs 的影响及其功能的机制知之甚少。为了研究这个问题，我们通过流式细胞术分析了 ST2 细胞（一种鼠骨髓来源的基质细胞系）和鼠原代骨髓来源的基质细胞中中性粒细胞的摄取情况。转录分析表明，MSCs 具有进行吞噬作用的必要受体和内部处理机制，其中 Axl 和 Tyro3 作为主要受体，而 MerTK 不表达。此外，无论凋亡靶标如何，这些受体的表达都受到吞噬作用行为的调节。来自人骨髓的 MSC 也表现出吞噬作用，表明 MSC 的吞噬作用是保守的。所有 MSC 的吞噬作用均损害成骨细胞分化。转录分析和功能测定表明，吞噬作用后 MSC 的线粒体功能下调。实验中，吞噬作用诱导 MSC 中线粒体分裂。在 MSC 中，通过药理学抑制线粒体分裂不仅降低了吞噬作用活性，而且挽救了成骨细胞分化，表明吞噬作用介导的线粒体重塑在调节 MSC 分化中起着关键作用。这项工作描述了 MSCs 在 BMME 中作为非专业吞噬细胞的新功能，并表明 MSC 的吞噬作用在指导线粒体重塑和 MSC 分化中起着关键作用。因此，MSC 的吞噬作用可能是一种新的功能障碍和衰老机制。由于我们在人 MSC 中的数据表明 MSC 的吞噬作用是保守的，因此 MSC 的吞噬作用的后果可能会影响这些细胞在人类骨骼中的行为，包括衰老、癌症和其他疾病状态下的骨髓重塑和骨质流失。
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