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Hematopoietic Stem Cells from Fancc^-/- Mice Have Lower Growth and Differentiation Potential in Response to Growth Factors

Unité de génétique humaine et moléculaire, CHUQ-Hôpital St-François d’Assise, Québec, Québec, Canada; Department of Pediatrics, Laval University, Québec, Québec, Canada

Key Words. Fanconi anemia • Stem cells • CD34⁺ • Fancc mouse model

Madeleine Carreau, Ph.D., Unité de génétique humaine et moléculaire, CHUQ-Hôpital St-François d’Assise, 10 rue de l’Espinay, Québec, Québec, Canada, G1L 3L5. Telephone: 418-525-4402; Fax: 418-525-4195; e-mail: madeleine.carreau{at}crsfa.ulaval.ca

Fanconi anemia (FA) is a complex recessive genetic disease characterized by progressive bone marrow (BM) failure. We have previously shown that stem cells from the FA group C mouse model have lower long-term primary and secondary reconstitution ability, and that bone marrow of Fancc^-/- mice contained fewer lineage-negative (Lin^-)Thy1.2^lowSca-1⁺c-kit⁺ CD34⁺ cells but normal levels of Lin^-Thy1.2^lowSca-1⁺c-kit⁺CD34^- primitive cells. These data suggest that CD34⁺ primitive cells have either a lower growth or differentiation potential, or that these cells have greater apoptosis levels. To investigate the role Fancc might have on the growth and differentiation potentials of primitive hematopoietic stem cells, we used a single-cell culture system and monitored cell viability, doubling potential, and apoptosis levels of Fancc^-/- primitive Lin^-Thy1.2^-Sca-1⁺ (LTS)-CD34⁺ and LTS-CD34^- stem cells. Results showed that Fancc^-/- LTS-CD34^- and LTS-CD34⁺ cells had altered growth and apoptosis responses to combinations of stimulatory cytokines, most dramatically in response to a combination of factors that included interleukin-3 (IL-3) and IL-6. In addition, Fancc^-/- LTS-CD34^- and LTS-CD34⁺ cells showed a lower differentiation potential than Fancc^+/+ cells. These results support a role for Fancc in the growth and differentiation of primitive hematopoietic cells and suggest that an altered response to stimulatory cytokines may contribute to BM aplasia in FA patients.

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