Quiescence of hematopoietic stem cells and maintenance of the stem cell pool is not dependent on TGF-beta signaling in vivo.
OBJECTIVE
Maintained quiescence of hematopoietic stem cells (HSCs) is of critical importance to prevent premature exhaustion of the stem cell pool under conditions of hematopoietic stress. The growth inhibitory cytokine transforming growth factor beta (TGF-beta) has been shown to play a critical role in maintaining quiescence of HSCs in vitro. Here, we have used conditional knockout mice for the TGF-beta type I receptor (TbetaRI) to ask whether the naturally quiescent state of HSCs in vivo is dependent on TGF-beta signaling and thus whether TGF-beta serves as a protective factor for the stem cell pool during conditions of stress.


METHODS
TbetaRI null and control bone marrow chimeras were subjected to repeated treatments with the cell cycle-specific cytotoxic drug 5-fluorouracil (5-FU) and surviving HSCs were assayed by competitive transplantation experiments. Exhaustion of stem cells was provoked by serially transplanting TGF-beta signaling-deficient as well as normal BM cells into lethally irradiated recipients, which were monitored for survival.


RESULTS
Surprisingly, we found that TGF-beta receptor-deficient HSCs have similar susceptibility, compared to controls, to repeated 5-FU treatments, indicative of normally maintained quiescence in these cells. Likewise, hematopoietic failure occurred at similar stages in serially transplanted recipients of TbetaRI null and control BM, respectively, demonstrating normal consumption of the stem cell pool during hematopoietic stress.


CONCLUSIONS
These findings clearly demonstrate that, despite a key role in vitro, TGF-beta does not provide the necessary signal that induces the quiescent state of HSCs and maintains the stem cell pool in vivo.
Larsson
Jonas
J
Department of Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden.
Blank
Ulrika
U
Klintman
Jenny
J
Magnusson
Mattias
M
Karlsson
Stefan
S
D000818:Animals; D002455:Cell Division; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D005472:Fluorouracil