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SPARC is dispensable for murine hematopoiesis, despite its suspected pathophysiological role in 5q-myelodysplastic syndrome

Leukemia volume 26, pages 2416–2419 (2012)Cite this article

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All mature blood cell types arise from a limited number of hematopoietic stem cells (HSCs). HSCs sustain hematopoiesis throughout the lifetime of an individual and any insult to them can lead to severe pathologies. Elucidating the molecular mechanisms that govern the maintenance and differentiation of HSCs is critical to understanding their role in hematological pathologies. In a search for novel regulators of HSCs, we selected SPARC (secreted protein acidic and rich in cysteine, also known as Osteonectin and BM40), because it was identified as one of the candidate regulators of HSCs by molecular profiling of differentiating hematopoietic cells in an in vitro model system.1 Several lines of evidence have also indicated an important role for SPARC in hematopoiesis. In zebrafish, a knockdown of SPARC resulted in lower numbers of circulating blood cells in developing embryos.2 In a murine model, SPARC deficiency resulted in thrombocytopenia and reduced erythroid colony formation.3 In humans, SPARC is transcriptionally silenced in acute myeloid leukemia patients and in cell lines with mixed lineage leukemia rearrangements.4 SPARC maps to the deleted region in 5q-myelodysplastic syndrome (MDS), an HSC disorder. With indications that SPARC may have a role in the hematopoietic system, we aimed to elucidate its role in the regulation of HSCs, as HSCs have not been characterized in the SPARC null mice.

SPARC is a glycoprotein that binds calcium and interacts with members of the extracellular matrix including collagens and thrombospodin. SPARC is expressed in a variety of tissues undergoing rapid turnover and is a major component of the bone. SPARC expression is associated with cell proliferation, migration, changes in morphology, matrix-remodeling and cell–cell interactions, although the precise function of the gene still remains unknown.5 SPARC knockout mice (SPARC−/−) are viable and fertile but display a number of abnormalities, including increased deposition of fat, highly contractile skin, alterations in wound healing and an altered response to tumor growth, most severe of which are osteopenia and early onset cataract.6, 7 SPARC−/− mice generated previously by the targeted mutation of exon 6 that completely lacked SPARC mRNA and protein6 were used in this study to carry out functional assays for HSCs.

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Acknowledgements

We thank Professor Sir Martin Evans for providing the SPARC knockout mice and the personnel at BMC animal facility for taking care of them. We thank Jonas Larsson, Jorg Cammenga and Ewa Sitnicka for valuable discussions and Zhi Ma for expert advice on Flow cytometry. This work was supported by Hemato-Linne grant (Swedish Research Council Linneas), the Swedish Cancer Foundation (Cancerfonden), the Swedish Children’s Cancer Society (SK), the Swedish Medical Research Council (SK), the Tobias Prize awarded by the Royal Swedish Academy of Sciences financed by the Tobias Foundation and the EU project grants CONSERT, STEMEXPAND and PERSIST. KS was funded by the Wenner-Gren Foundation and The Tobias Foundation. The Lund Stem Cell Center was supported by a Center of Excellence grant in life sciences from the Swedish Foundation for Strategic research.

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  1. Department of Molecular Medicine and Gene Therapy, Lund Strategic Center for Stem Cell Biology, Lund, Sweden

    K Siva, P Jaako, K Miharada, E Rörby, G Karlsson & S Karlsson

  2. University Hospital, Lund, Sweden

    M Ehinger

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  1. K Siva
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Correspondence to S Karlsson.

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Siva, K., Jaako, P., Miharada, K. et al. SPARC is dispensable for murine hematopoiesis, despite its suspected pathophysiological role in 5q-myelodysplastic syndrome. Leukemia 26, 2416–2419 (2012). https://doi.org/10.1038/leu.2012.97

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