Efferocytosis by Bone Marrow Stromal Cells and Bone Aging

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Efferocytosis by bone marrow stromal cells and bone aging Pre-clinical studies show that senescent bone marrow-derived mesenchymal stromal (a.k.a. stem) cells (MSCs) and osteolineage cells contribute to age-dependent bone loss and bone marrow failure. Therefore, the identification of novel mechanisms that accelerate MSC dysfunction could enable mechanistic approaches to degenerative processes that impact the skeleton. While a handful of in vitro studies previously demonstrated MSCs’ ability to phagocytose apoptotic cells (efferocytosis), matrix, pathogens and metal particles, whether efferocytosis by MSCs impacts their function and bone maintenance is not known. We found that bone marrow MSCs indeed efferocytose apoptotic neutrophils in vivo. Preliminary data from adult mice with transgenic overexpression of the direct phosphatidyl serine receptor BAI1 in MSCs suggest that chronic low dose enhancement of efferocytosis by MSCs may be beneficial to skeletal health. We also found that, in aged mice, efferocytosis by MSCs is significantly increased. Moreover, transcriptional and functional preliminary data in vitro suggest that excessive efferocytosis by MSCs decreases osteoblastic differentiation and promotes senescence. Since efferocytosis is accompanied by oxidative stress and mitochondrial changes, which we previously found to modulate osteoblastic differentiation, mitochondrial disruption may mediate functional changes in MSCs that clear high numbers of apoptotic cells. Based on these data, we hypothesize that phagocytosis by MSCs is an important component of osteoimmunology; however when pathologically increased in aging, it causes MSC oxidative stress, mitochondrial dysfunction and senescence, thus contributing to bone loss. To test this, using aging and genetic models, we will 1) determine the mechanism of MSC efferocytosis; 2) define the pathogenic mechanisms induced by efferocytosis in MSCs; and 3) establish the role of efferocytosis by MSCs in normal osteoimmunology and in aged bone. Defining the role of facultative phagocytosis/efferocytosis in metabolic changes and senescence in MSC and their relevance to human aging and disease will provide innovative, actionable strategies impacting degenerative disorders that target the skeleton.