Stromal cell-derived factor-1 (SDF-1), a CXC chemokine family member, is constitutively expressed by bone marrow (BM) stromal cells and is present in many other tissues.1-3 SDF-1 was initially identified as a potent chemoattractant for lymphocytes, monocytes, and as an enhancer of B cell proliferation.1-3 It also appears to play a role in lymphocyte trafficking and hematopoietic progenitor cell (HPC) and stem cell (HSC) homing.4 These effects are mediated through its receptor, CXCR4.5
Homing of HSCs from the peripheral circulation to the BM is a multi-step process. It involves sequential interaction of CD34+ HPCs with adhesion molecules expressed on BM endothelial cells and specific BM chemokine expression. SDF-1 plays a key role in providing these directional cues, orchestrating CD34+ cell migration and homing from the fetal liver into the BM.4,6-8 Both SDF-19 and CXCR410,11 knockouts result in BM hematopoiesis defects, whereas fetal liver hematopoietic activity remains unaltered. SDF-1 and CXCR4 are also essential to human severe combined immunodeficient (SCID) stem cell engraftment and repopulation by nonobese diabetic (NOD)/SCID mice.7,12
Based on these results, Hattori et al.13 performed experiments which demonstrate that elevation of SDF-1 levels in peripheral blood result in HPC and HSC mobilization to the peripheral circulation with a concurrent decrease within the BM. The mobilization effects of circulating SDF-1 were examined by intravenously injecting SCID mice with adenoviral (Ad) vectors expressing SDF-1 (AdSDF1). Ad vector (AdNull) and Ad vector expressing MIP-3 alpha (AdMIP3 alpha) were employed as controls. Injection of AdSDF1 enabled constitutive production of high levels of SDF-1 (2.5 ng/mL) necessary to reverse the BM barrier gradient and force CXCR4-expressing cells, including HPCs and HSCs, to exit the BM. The increased number of HPCs were monitored by seeding cells collected from BM, spleen, and peripheral blood in colony-forming assays and scoring the colony forming units (CFUs). AdSDF1-induced migration of significant numbers of colony-forming units-spleen (CFU-S). Both AdNull and AdMIP3 alpha controls were found to be ineffective in mobilizing significant numbers of HPCs and HSCs. This demonstrates that AdSDF1-induced mobilization was not a result of Ad infection. Furthermore, injection of as few as 1 x 105 PBMNCs from an AdSDF1, but not AdNull, infected mouse into a lethally irradiated recipient mouse resulted in reconstitution of hematopoiesis. These results strongly suggest SDF-1 mobilized cell subsets have stem cell potential. Consequently, knowing that successful peripheral blood stem cell collection and BM transplantation require mobilization of HSCs with repopulating capacity, systemic over-expression of SDF-1 may provide a novel HSC mobilization regimen prior to BM transplantation.
- Tashiro, K. et al. (1993) Science 261:600.
- Nagasawa, T. (1994) Proc. Natl. Acad. Sci. USA 91:2305.
- Bluel, C. et al. (1996) J. Exp. Med. 184:1101.
- Aiuti, A. et al. (1997) J. Exp. Med. 185:111.
- Bluel, C. et al. (1996) Nature 382:829.
- Kim, C.H. and H.E. Broxmeyer (1998) Blood 91:100.
- Peled, A. et al. (1999) Science 283:845.
- Mohle, R. et al. (1998) Blood 91:4523.
- Nagasawa, T. et al. (1996) Nature 382:635.
- Zuo, Y.R. et al. (1998) Nature 393:595.
- Ma, Q. et al. (1998) Proc. Nat. Acad. Sci. USA 95:9448.
- Jo, D-Y. et al. (2000) J. Clin. Invest. 105:101.
- Hattori, K. et al. (2001) Blood 97:3354.