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Publication - Professor Paolo Madeddu

    MCP-1 Feedback Loop Between Adipocytes and Mesenchymal Stromal Cells Causes Fat Accumulation and Contributes to Hematopoietic Stem Cell Rarefaction in the Bone Marrow of Patients With Diabetes

    MCP-1 Feedback Loop and Bone Marrow MSCs

    Citation

    Ferland-McCollough, D, Maselli, D, Spinetti, G, Sambataro, M, Sullivan, N, Blom, A & Madeddu, P, 2018, ‘MCP-1 Feedback Loop Between Adipocytes and Mesenchymal Stromal Cells Causes Fat Accumulation and Contributes to Hematopoietic Stem Cell Rarefaction in the Bone Marrow of Patients With Diabetes: MCP-1 Feedback Loop and Bone Marrow MSCs’. Diabetes.

    Abstract

    Fat accumulates in bone marrow (BM) of patients with
    diabetes. In this study, we investigated the mechanisms
    and consequences of this phenomenon. BM-mesenchymal
    stromal cells (BM-MSCs) from patients with type 2
    diabetes (T2D) constitutively express adipogenic markers
    and robustly differentiate into adipocytes (ADs) upon
    in vitro induction as compared with BM-MSCs from subjects
    without diabetes. Moreover, BM-ADs from subjects
    with T2D (T2D BM-ADs) paracrinally stimulate a transcriptional
    adipogenic program in BM-MSCs. Antagonism of
    MCP-1, a chemokine pivotally expressed in T2D BM-ADs,
    prevented the T2D BM-AD secretome from converting
    BM-MSCs into ADs.Mechanistic validation of human data
    was next performed in an obese T2D mouse model. Systemic
    antagonism of MCP-1 improved metabolic control,
    reduced BM fat, and increased osteocyte density. It also
    indirectly re-established the abundance of long-term
    versus short-term hematopoietic stem cells. We reveal
    a diabetic feedback loop in which 1) BM-MSCs are constitutively
    inclined to make ADs, and 2) mature BM-ADs,
    via secreted MCP-1, relentlessly fuel BM-MSC determination
    into new fat. Pharmacological inhibition of MCP-1
    signaling can contrast this vicious cycle, restoring, at least
    in part, the balance between adipogenesis and hematopoiesis
    in BM from subjects with T2D.

    Full details in the University publications repository