Lnk negatively regulates self-renewal of hematopoietic stem cells by modifying thrombopoietin-mediated signal transduction

• DOI: 10.1073/pnas.0606238104
• Publication Date: 2007-02-07T08:59:21Z
• Authors: Jun Seita; Hideo Ema; Jun Ooehara; Satoshi Yamazaki; Yuko Tadokoro; Akiko Yamasaki; Koji Eto; Satoshi Takaki; Kiyoshi Takatsu; Hiromitsu Nakauchi
• Keywords: Hematopoietic stem cell; Thrombopoiesis

One of the central tasks stem cell biology is to understand molecular mechanisms that control self-renewal in cells. Several cytokines are implicated as crucial regulators hematopoietic cells (HSCs), but little known about intracellular signaling for HSC self-renewal. To address this issue, we attempted clarify how potential enhanced HSCs without adaptor molecule Lnk, Lnk-deficient mice expanded number >10-fold because their increased potential. We show Lnk negatively regulates by modifying thrombopoietin (TPO)-mediated signal transduction. Single-cell cultures showed hypersensitive TPO. Competitive repopulation revealed long-term repopulating activity increases HSCs, not WT when these cultured presence TPO with or factor. transplantation each paired daughter indicated a combination factor and efficiently induces symmetrical division HSCs. Newly developed single-cell immunostaining demonstrated significant enhancement both p38 MAPK inactivation STAT5 Akt activation after stimulation Our results suggest balance positive negative signals downstream from plays role regulation probability In general, likewise, fate may be determined combinational changes multiple transduction pathways.