Scl regulates the quiescence and the long-term competence of hematopoietic stem cells.
The majority of long-term reconstituting hematopoietic stem cells (LT-HSCs) in the adult is in G(0), whereas a large proportion of progenitors are more cycling. We show here that the SCL/TAL1 transcription factor is highly expressed in LT-HSCs compared with short-term reconstituting HSCs and progenitors and that SCL negatively regulates the G(0)-G(1) transit of LT-HSCs. Furthermore, when SCL protein levels are decreased by gene targeting or by RNA interference, the reconstitution potential of HSCs is impaired in several transplantation assays. First, the mean stem cell activity of HSCs transplanted at approximately 1 competitive repopulating unit was 2-fold decreased when Scl gene dosage was decreased. Second, Scl(+/-) HSCs were at a marked competitive disadvantage with Scl(+/+) cells when transplanted at 4 competitive repopulating units equivalent. Third, reconstitution of the stem cell pool by adult HSCs expressing Scl-directed shRNAs was decreased compared with controls. At the molecular level, we found that SCL occupies the Cdkn1a and Id1 loci in primary hematopoietic cells and that the expression levels of these 2 regulators of HSC cell cycle and long-term functions are sensitive to Scl gene dosage. Together, our observations suggest that SCL impedes G(0)-G(1) transition in HSCs and regulates their long-term competence.
Institute of Research in Immunology and Cancer (IRIC), Montreal, QC, Canada.
Julie
J
Lacombe
Sabine
S
Herblot
Shanti
S
Rojas-Sutterlin
André
A
Haman
Stéphane
S
Barakat
Norman N
NN
Iscove
Guy
G
Sauvageau
Trang
T
Hoang
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D016193:G1 Phase / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D017370:Interleukin-11 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D034622:RNA Interference; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D019089:Stem Cell Factor / Q000494:pharmacology; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051798:Inhibitor of Differentiation Protein 1; D017370:Interleukin-11; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D019089:Stem Cell Factor; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C493957:Cdkn1a protein, mouse; C497455:Idb1 protein, mouse; C489366:Tal1 protein, mouse