2013 – A LABEL-FREE, HIGH-THROUGHPUT PHENOTYPIC SCREEN OF ADIPOCYTIC DIFFERENTIATION MODULATORS TO ACCELERATE HEMATOPOIETIC RECOVERY

Bone marrow (BM) preadipocytes and adipocytes are part of the same differentiation axis and co-exist within this organ with hematopoietic cells. Mature adipocytes can slow down hematopoietic progenitor proliferation whereas pre-adipocytes efficiently support their growth, suggesting that modulating the adipocytic differentiation axis could steer hematopoietic function. We used digital holographic microscopy to perform a label-free, high-throughput in vitro phenotypic screen of more than 4000 compounds to identify modulators of adipocytic differentiation. Candidate compounds were counter-screened for niche-mediated effects on hematopoietic proliferation. The screen identified calcipotriol, a vitamin D analogue. Treatment with calcipotriol remodeled adipocytes in a dose-dependent manner and increased hematopoietic progenitors in mice undergoing lethal irradiation followed by BM transplantation. Furthermore, treatment with calcipotriol rescued mortality in CXCL12 haplo-insufficient mice undergoing limiting-dose BM transplantation. Our approach provides a useful tool to study adipocyte biology, demonstrates the feasibility of modulating the adipocytic differentiation axis in the BM and indicates its potential role in clinically relevant conditions of high hematopoietic demand. Bone marrow (BM) preadipocytes and adipocytes are part of the same differentiation axis and co-exist within this organ with hematopoietic cells. Mature adipocytes can slow down hematopoietic progenitor proliferation whereas pre-adipocytes efficiently support their growth, suggesting that modulating the adipocytic differentiation axis could steer hematopoietic function. We used digital holographic microscopy to perform a label-free, high-throughput in vitro phenotypic screen of more than 4000 compounds to identify modulators of adipocytic differentiation. Candidate compounds were counter-screened for niche-mediated effects on hematopoietic proliferation. The screen identified calcipotriol, a vitamin D analogue. Treatment with calcipotriol remodeled adipocytes in a dose-dependent manner and increased hematopoietic progenitors in mice undergoing lethal irradiation followed by BM transplantation. Furthermore, treatment with calcipotriol rescued mortality in CXCL12 haplo-insufficient mice undergoing limiting-dose BM transplantation. Our approach provides a useful tool to study adipocyte biology, demonstrates the feasibility of modulating the adipocytic differentiation axis in the BM and indicates its potential role in clinically relevant conditions of high hematopoietic demand.