Diabetes mellitus causes adiposopathy in bone marrow
: investigation of the underpinning cellular and molecular mechanisms

  • Yue Gu

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Background: Lipotoxicity contributes to local and systemic damage. Senolytic drugs eliminate senescent preadipocytes. However, their effects on fat in heart and bone marrow (BM) remain unknown. Tyrosine kinase inhibitors (TKI) showed therapeutic potential for treating non-malignant disorders such as cardiac hypertrophy, atherosclerosis, and arthritis. Dasatinib is a second-generation TKI endowed with senolytic activity. It is unknown whether Dasatinib reduces adiposity in BM and the heart.
Hypothesis and Aims: Pericytes (PCs) are primary adipocyte sources among BM stromal cells. BM senescence causes the adipogenic commitment of PCs. Dasatinib reduces fat deposits in the BM and heart in a diabetic murine model, positively affecting organ function.

Methods and results: Human CD34neg CD45neg CD146pos pericytes (hBM-PCs) were sorted from BM mesenchymal stromal cells (hBM-MSCs) by immunomagnetic beads. HBM-PCs showed a special propensity to differentiate into adipocytes. Dasatinib reduced hBM-PCs viability and adipocyte differentiation. In a randomised, operator-blinded study, Dasatinib (5 mg/kg) or vehicle (10% DMSO + 90% PEG300) was given by gavage to T2DM, obese 21-week-old male mice. Animals were sacrificed at 1 (Total administrations = 2) or 4 (Total administrations = 4) weeks thereafter. The short-term treatment reduced the fat content in heart and BM but did not improve heart anatomy and function. The long-term treatment reduced steatosis, fibrosis, and levels of senescence marker p16INK4a in the heart. It also improved left ventricle diastolic indexes. Moreover, Dasatinib reduced BM adiposity but no other fat depots. In vitro, Dasatinib treatment of murine BM-MSCs reduced the expression of p21Waf1/Cip1.

Conclusion: PCs are the primary source of adipocytes in human BM. Dasatinib reduces the PC adipogenesis commitment. Dasatinib prevented fat accumulation in the heart and BM and cell senescence in the heart of T2DM mice. Prolonged treatment reduced adiposity and improved cardiac function. These findings demonstrate that pulsed administration of Dasatinib benefits diabetic cardiomyopathy.
Date of Award16 Jan 2024
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorPaolo Madeddu (Supervisor) & Harry H Mellor (Supervisor)

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