Phagocytosis by stroma confounds coculture studies

Herbst, Sophie A.; Stolarczyk, Marta; Becirovic, Tina; Czernilofsky, Felix; Liu, Yi; Kolb, Carolin; Knoll, Maximilian; Herling, Marco; Müller‐Tidow, Carsten; Dietrich, Sascha

doi:10.1016/j.isci.2021.103062

Cited by 2 publications

(4 citation statements)

References 32 publications

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“…However, MSCs had been reported to contribute to phagocytosis in the embryo [ 24 ]. Follow-up studies in vitro confirmed phagocytosis and efferocytosis capacity of MSC [ 16 – 23 , 25 , 26 ]. Given the metabolic and mitochondrial impact of efferocytosis in macrophages [ 6 ], we reasoned that MSC efferocytosis may have a metabolic impact, and that it may inhibit their differentiation.…”

Section: Discussionmentioning

confidence: 91%

“…Previous studies have noted that MSCs can phagocytose bacteria [16,17], metallic particles from prosthetics [18,19,22], collagen [23], and apoptotic cells [20,21,[24][25][26]. However, dynamics and impact of this MSC activity remain poorly understood.…”

Section: Mesenchymal Stromal Cells Participate In Efferocytosismentioning

confidence: 99%

“…Many organs and systems have supporting, non-professional phagocytes that can be recruited to aid in the clearance of dead and dying cells and inflammation [3,4,[12][13][14][15]. A handful of studies have shown that mesenchymal stromal cells (MSCs) are capable of both phagocytosis and efferocytosis and may play the role of the non-professional phagocyte within the BMME [16][17][18][19][20][21][22][23][24][25][26]. Under normal physiologic conditions, MSCs give rise to bone-forming osteoblasts and are critical for maintaining skeletal homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling

Quarato

Salama

et al. 2023

Cell Death Dis

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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.

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Section: Discussionmentioning

confidence: 91%

Section: Mesenchymal Stromal Cells Participate In Efferocytosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling

Quarato

Salama

et al. 2023

Cell Death Dis

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“…Cells with a calcein intensity above a certain threshold and with PI intensities below a certain threshold were classified as alive. To avoid a possible influence of phagocytosis on relative percentages of alive cells (Herbst et al , 2021), absolute counts of alive CLL cells were used for all further analyses. These viabilities were normalised by division through viabilities in DMSO controls.…”

Section: Methodsmentioning

confidence: 99%

Comparing the value of mono- versus coculture for high-throughput compound screening in hematological malignancies

Herbst

Kim

Schitter

et al. 2022

Preprint

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The bone marrow microenvironment modulates treatment response in blood cancers but a systematic assessment of anticancer drug effects in the context of this protective niche has been missing. To fill this gap, we established an ex-vivo model that enables high-throughput compound screening in leukemia-stroma coculture. We applied 50 compounds to 108 patient samples with hematological malignancies in monoculture and coculture with bone marrow stromal cells and measured cellular phenotypes via automated confocal microscopy. Stromal coculture conferred resistance to 52% of compounds in chronic lymphocytic leukemia (CLL) and to 36% of compounds in acute myeloid leukemia (AML). Although a partial loss in efficacy was observed for a considerable number of investigated drugs, responses to many of the drugs were comparable between mono- and cocultures. This suggests that large-scale monoculture drug perturbation studies might be sufficient for the purpose of first-line screening. However, our study also uncovered a substantial heterogeneity of stromal protection across the probed samples and compounds, which highlights the importance of validating the findings of monoculture screens in stroma coculture models.

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Phagocytosis by stroma confounds coculture studies

Cited by 2 publications

References 32 publications

Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling

Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling

Comparing the value of mono- versus coculture for high-throughput compound screening in hematological malignancies

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