Identification of a stroma-mediated Wnt/beta-catenin signal promoting self-renewal of hematopoietic stem cells in the stem cell niche.
With contrasting observations on the effects of beta-catenin on hematopoietic stem cells (HSCs), the precise role of Wnt/beta-catenin signals on HSC regulation remains unclear. Here, we show a distinct mode of Wnt/beta-catenin signal that can regulate HSCs in a stroma-dependent manner. Stabilization of beta-catenin in the bone marrow stromal cells promoted maintenance and self-renewal of HSCs in a contact-dependent manner, whereas direct stabilization in hematopoietic cells caused loss of HSCs. Interestingly, canonical Wnt receptors and beta-catenin accumulation were predominantly enriched in the stromal rather than the hematopoietic compartment of bone marrows. Moreover, the active form of beta-catenin accumulated selectively in the trabecular endosteum in "Wnt 3a-stimulated" or "irradiation-stressed," but not in "steady-state" marrows. Notably, notch ligands were induced in Wnt/beta-catenin activated bone marrow stroma and downstream notch signal activation was seen in the HSCs in contact with the activated stroma. Taken together, Wnt/beta-catenin activated stroma and their cross-talk with HSCs may function as a physiologically regulated microenvironmental cue for HSC self-renewal in the stem cell niche.
Kim
Jin-A
JA
Catholic Cell Therapy Center and Department of Cellular Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Kang
Young-Ju
YJ
Park
Gyeongsin
G
Kim
Myungshin
M
Park
Young-Ok
YO
Kim
Hanjun
H
Leem
Sun-Hee
SH
Chu
In-Sun
IS
Lee
Jun-Seong
JS
Jho
Eek-Hoon
EH
Oh
Il-Hoan
IH
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D020239:Receptor Cross-Talk / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D055153:Stem Cell Niche / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D051153:Wnt Proteins; D051176:beta Catenin