Conditional deletion of STAT5 in adult mouse hematopoietic stem cells causes loss of quiescence and permits efficient nonablative stem cell replacement

• Published in: Blood Vol. 113; no. 20; pp. 4856 - 4865
• Main Authors: Wang, Zhengqi, Li, Geqiang, Tse, William, Bunting, Kevin D.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 14.05.2009; Americain Society of Hematology; American Society of Hematology
• Series: Hematopoiesis and Stem Cells
• Subjects: Adaptor Proteins, Signal Transducing; Adult Stem Cells - metabolism; Adult Stem Cells - physiology; Animals; Biological and medical sciences; Cell Proliferation; Gene Deletion; Gene Dosage - physiology; Hematologic and hematopoietic diseases; Hematopoiesis - genetics; Hematopoiesis and Stem Cells; Hematopoietic Stem Cell Mobilization - methods; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - physiology; Immune Tolerance - genetics; Leukocyte Common Antigens - genetics; Leukocyte Common Antigens - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphoproteins - genetics; STAT5 Transcription Factor - genetics; Transplantation Conditioning; Hematology; Transcription factor STAT5; Cell death; Stem cell; Adult animal; Hematopoietic cell; Deletion; Non myeloablative treatment; Quiescence
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-09-181107

Currently, there is a major need in hematopoietic stem cell (HSC) transplantation to develop reduced-intensity regimens that do not cause DNA damage and associated toxicities and that allow a wider range of patients to receive therapy. Cytokine receptor signals through c-Kit and c-Mpl can modulate HSC quiescence and engraftment, but the intracellular signals and transcription factors that mediate these effects during transplantation have not been defined. Here we show that loss of one allele of signal transducer and activator of transcription 5 (STAT5) in nonablated adult mutant mice permitted engraftment with wild-type HSC. Conditional deletion of STAT5 using Mx1-Cre caused maximal reduction in STAT5 mRNA (> 97%) and rapidly decreased quiescence-associated c-Mpl downstream targets (Tie-2, p57), increased HSC cycling, and gradually reduced survival and depleted the long-term HSC pool. Host deletion of STAT5 was persistent and permitted efficient donor long-term HSC engraftment in primary and secondary hosts in the absence of ablative conditioning. Overall, these studies establish proof of principle for targeting of STAT5 as novel transplantation conditioning and demonstrate, for the first time, that STAT5, a mitogenic factor in most cell types, including hematopoietic progenitors, is a key transcriptional regulator that maintains quiescence of HSC during steady-state hematopoiesis.