Loss of SPARC protects hematopoietic stem cells from chemotherapy toxicity by accelerating their return to quiescence.
Armin Ehninger, Tobias Boch, Hind Medyouf, Katja Müdder, Gertraud Orend, Andreas Trumpp
Author Information
Armin Ehninger: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; and.
Tobias Boch: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; and.
Hind Medyouf: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; and.
Katja Müdder: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; and.
Gertraud Orend: INSERM Unit 1109, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, University Strasbourg, LabEx Medalis, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France.
Andreas Trumpp: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany; and.
Around birth, hematopoietic stem cells (HSCs) expanding in the fetal liver migrate to the developing bone marrow (BM) to mature and expand. To identify the molecular processes associated with HSCs located in the 2 different microenvironments, we compared the expression profiles of HSCs present in the liver and BM of perinatal mice. This revealed the higher expression of a cluster of extracellular matrix-related genes in BM HSCs, with secreted protein acidic and rich in cysteine (SPARC) being one of the most significant ones. This extracellular matrix protein has been described to be involved in tissue development, repair, and remodeling, as well as metastasis formation. Here we demonstrate that SPARC-deficient mice display higher resistance to serial treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). Using straight and reverse chimeras, we further show that this protective effect is not due to a role of SPARC in HSCs, but rather is due to its function in the BM niche. Although the kinetics of recovery of the hematopoietic system is normal, HSCs in a SPARC-deficient niche show an accelerated return to quiescence, protecting them from the lethal effects of serial 5-FU treatment. This may become clinically relevant, as SPARC inhibition and its protective effect on HSCs could be used to optimize chemotherapy schemes.
