Contributions
Abstract: EP750
Type: E-Poster Presentation
Session title: Hematopoiesis, stem cells and microenvironment
Background
The hematopoietic stem cell (HSC) niche constitutes a complex bone marrow (BM) microenvironment that tightly controls HSC proliferation. Adipocytes have been shown to inhibit hematopoietic progenitor proliferation, but adiponectin-expressing cells are required for full HSC support and pre-adipocytes can efficiently support the growth of hematopoietic cells in culture. Given that specific bone marrow stromal cell (BMSC) subpopulations, preadipocytes, and adipocytes are part of the same differentiation axis, this apparently contradictory data suggests that the same precursor can generate cells with divergent hematopoietic-supportive capacity.
Aims
We thus hypothesized that pharmacological modulation of the adipocytic differentiation axis could inhibit bone marrow-derived adipocyte maturation and predict hematopoietic progenitor support.
Methods
To test this hypothesis, we performed devised high content phenotypic screening pipeline to identify modulators of adipocytic differentiation with increased hematopoietic support in the absence of exogenous cytokines. For in vivo validation of the screen, compounds were tested for their capacity to shorten aplasia post lethal irradiation and bone marrow transplantation. Specifically, the Prestwick Chemical Library of FDA-approved drugs, a library containing natural products and the library of chemicals generated from swiss academic laboratories were screened for their potential to prevent lipidation.
Results
After confirmation screen and dose-response determination, 49 inhibitors were selected. RNA-seq further classified compounds inhibiting adipocyte-specific gene expression as well as maintaining expression of hematopoiesis-supportive cytokines. Functional in vitro assays further identified a specific vitamin D analog as the strongest niche modulator, and transcriptome analysis revealed a CAR-like phenotype. In vivo administration significantly decreased both the adipocyte size and content of bones at day 18 post BM transplantation, increased platelet recovery and increased total number of CFU per leg.
Conclusion
Our pipeline allowed for the screening of more than 4000 compounds and identified a vitamin D derivative as a first candidate to induce a CAR-like phenotype and accelerate hematopoietic recovery in radio/chemotherapy-induced aplasia.
Keyword(s): Hematopoiesis, Microenvironment, Stromal cell
Abstract: EP750
Type: E-Poster Presentation
Session title: Hematopoiesis, stem cells and microenvironment
Background
The hematopoietic stem cell (HSC) niche constitutes a complex bone marrow (BM) microenvironment that tightly controls HSC proliferation. Adipocytes have been shown to inhibit hematopoietic progenitor proliferation, but adiponectin-expressing cells are required for full HSC support and pre-adipocytes can efficiently support the growth of hematopoietic cells in culture. Given that specific bone marrow stromal cell (BMSC) subpopulations, preadipocytes, and adipocytes are part of the same differentiation axis, this apparently contradictory data suggests that the same precursor can generate cells with divergent hematopoietic-supportive capacity.
Aims
We thus hypothesized that pharmacological modulation of the adipocytic differentiation axis could inhibit bone marrow-derived adipocyte maturation and predict hematopoietic progenitor support.
Methods
To test this hypothesis, we performed devised high content phenotypic screening pipeline to identify modulators of adipocytic differentiation with increased hematopoietic support in the absence of exogenous cytokines. For in vivo validation of the screen, compounds were tested for their capacity to shorten aplasia post lethal irradiation and bone marrow transplantation. Specifically, the Prestwick Chemical Library of FDA-approved drugs, a library containing natural products and the library of chemicals generated from swiss academic laboratories were screened for their potential to prevent lipidation.
Results
After confirmation screen and dose-response determination, 49 inhibitors were selected. RNA-seq further classified compounds inhibiting adipocyte-specific gene expression as well as maintaining expression of hematopoiesis-supportive cytokines. Functional in vitro assays further identified a specific vitamin D analog as the strongest niche modulator, and transcriptome analysis revealed a CAR-like phenotype. In vivo administration significantly decreased both the adipocyte size and content of bones at day 18 post BM transplantation, increased platelet recovery and increased total number of CFU per leg.
Conclusion
Our pipeline allowed for the screening of more than 4000 compounds and identified a vitamin D derivative as a first candidate to induce a CAR-like phenotype and accelerate hematopoietic recovery in radio/chemotherapy-induced aplasia.
Keyword(s): Hematopoiesis, Microenvironment, Stromal cell