Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Orschell, Christie M.; Borneo, Jovencio; Munugalavadla, Veerendra; Ma, Peilin; Sims, Emily; Ramdas, Baskar; Yoder, Mervin C.; Kapur, Reuben

doi:10.1016/j.exphem.2008.01.002

« Previous Next »Experimental Hematology
Volume 36, Issue 5 , Pages 655-666, May 2008

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells

Christie M. Orschell
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Ind., USA
- Drs. Orschell and Borneo contributed equally to this work and should be considered co-first authors.
Jovencio Borneo
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind., USA
- Drs. Orschell and Borneo contributed equally to this work and should be considered co-first authors.
Veerendra Munugalavadla
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind., USA
- Drs. Munugalvadla and Ma contributed equally to this work and should be considered co-second authors.
Peilin Ma
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind., USA
- Drs. Munugalvadla and Ma contributed equally to this work and should be considered co-second authors.
Emily Sims
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind., USA
Baskar Ramdas
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind., USA
Mervin C. Yoder
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind., USA
- Department of Molecular Biology and Biochemistry, Indiana University School of Medicine, Indianapolis, Ind., USA
Reuben Kapur
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Ind., USA
- Department of Molecular Biology and Biochemistry, Indiana University School of Medicine, Indianapolis, Ind., USA
- Department of Medical and Molecular Genetics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind., USA
- Offprint requests to: Reuben Kapur, Ph.D., Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Cancer Research Institute, 1044 W. Walnut Street, Room 425, Indianapolis, IN 46202

Received 4 December 2007; received in revised form 14 January 2008; accepted 15 January 2008. published online 17 March 2008.

Objective

Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells.

Results

Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1⁺Lin⁻ cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo. Interestingly, a significant increase in expression of adhesion molecules, known to coincide with the homing potential of wild-type bone marrow cells is also observed on the surface of SFK^−/− cells, although, this increase did not affect the homing potential of more primitive Lin⁻Sca-1⁺ SFK^−/− cells. The stem cell−repopulating defect observed in mice transplanted with SFK^−/− bone marrow cells is due to the loss of Lyn Src kinase, because deficiency of Lyn, but not Hck or Fgr, recapitulated the long-term stem cell defect observed in mice transplanted with SFK^−/− bone marrow cells.

Conclusions

Taken together, our results demonstrate an essential role for Lyn kinase in positively regulating the long-term and multilineage engraftment of stem cells, which is distinct from its role in mature B cells and myeloid cells.