TIMP-3 recruits quiescent hematopoietic stem cells into active cell cycle and expands multipotent progenitor pool.
Regulating transition of hematopoietic stem cells (HSCs) between quiescent and cycling states is critical for maintaining homeostasis of blood cell production. The cycling states of HSCs are regulated by the extracellular factors such as cytokines and extracellular matrix; however, the molecular circuitry for such regulation remains elusive. Here we show that tissue inhibitor of metalloproteinase-3 (TIMP-3), an endogenous regulator of metalloproteinases, stimulates HSC proliferation by recruiting quiescent HSCs into the cell cycle. Myelosuppression induced TIMP-3 in the bone marrow before hematopoietic recovery. Interestingly, TIMP-3 enhanced proliferation of HSCs and promoted expansion of multipotent progenitors, which was achieved by stimulating cell-cycle entry of quiescent HSCs without compensating their long-term repopulating activity. Surprisingly, this effect did not require metalloproteinase inhibitory activity of TIMP-3 and was possibly mediated through a direct inhibition of angiopoietin-1 signaling, a critical mediator for HSC quiescence. Furthermore, bone marrow recovery from myelosuppression was accelerated by over-expression of TIMP-3, and in turn, impaired in TIMP-3-deficient animals. These results suggest that TIMP-3 may act as a molecular cue in response to myelosuppression for recruiting dormant HSCs into active cell cycle and may be clinically useful for facilitating hematopoietic recovery after chemotherapy or ex vivo expansion of HSCs.
Nakajima
Hideaki
H
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. hnakajim@sc.itc.keio.ac.jp
Ito
Miyuki
M
Smookler
David S
DS
Shibata
Fumi
F
Fukuchi
Yumi
Y
Morikawa
Yoshihiro
Y
Ikeda
Yuichi
Y
Arai
Fumio
F
Suda
Toshio
T
Khokha
Rama
R
Kitamura
Toshio
T
D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D017353:Gene Deletion; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D042683:Angiopoietin-1; D019717:Tissue Inhibitor of Metalloproteinase-3