Indispensable role of Galectin-3 in promoting quiescence of hematopoietic stem cells

• Published in: Nature communications 2021-04, Vol.12 (1), p.2118-2118, Article 2118
• Main Authors: Jia, Weizhen, Kong, Lingyu, Kidoya, Hiroyasu, Naito, Hisamichi, Muramatsu, Fumitaka, Hayashi, Yumiko, Hsieh, Han-Yun, Yamakawa, Daishi, Hsu, Daniel K., Liu, Fu-Tong, Takakura, Nobuyuki
• Format: Article
• Language: English
• Subjects: 631/532/1542; 631/532/2443; 631/80/86/2368; 96; 96/31; Adult Stem Cells - physiology; Animals; Bone marrow; Cell cycle; Cell Cycle - physiology; Cell Differentiation - genetics; Cell Line, Tumor; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Female; Galactose; Galectin 3 - genetics; Galectin 3 - metabolism; Galectin-3; Hematopoiesis; Hematopoiesis - genetics; Hematopoietic stem cells; Hematopoietic Stem Cells - physiology; Homeostasis; Humanities and Social Sciences; Mice; Mice, Knockout; Models, Animal; multidisciplinary; Receptor, TIE-2 - metabolism; Receptors, Thrombopoietin - metabolism; Science; Science (multidisciplinary); Sp1 Transcription Factor - metabolism; Stem cell transplantation; Stem cells; Transcription; Transcriptional Activation; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22346-2

Hematopoietic stem cells (HSCs) in adult bone marrow (BM) are usually maintained in a state of quiescence. The cellular mechanism coordinating the balance between HSC quiescence and differentiation is not fully understood. Here, we report that galactose-binding lectin-3 (galectin-3; Gal-3) is upregulated by Tie2 or Mpl activation to maintain quiescence. Conditional overexpression of Gal-3 in mouse HSCs under the transcriptional control of Tie2 or Vav1 promoters (Gal-3 Tg) causes cell cycle retardation via induction of p21. Conversely, the cell cycle of long-term repopulating HSCs (LT-HSCs) in Gal-3-deficient (Gal-3 -/- ) mice is accelerated, resulting in their exhaustion. Mechanistically, Gal-3 regulates p21 transcription by forming a complex with Sp1, thus blocking cell cycle entry. These results demonstrate that Gal-3 is a negative regulator of cell-cycling in HSCs and plays a crucial role in adult hematopoiesis to prevent HSC exhaustion. Long term haematopoitic stem cells (LT-HSCs) are in a quiescent state during homeostasis, which is critical for their maintenance. Here, the authors show that Gal-3 expression in LT-HSCs is induced in response to Tie2 and Mpl and is both necessary and sufficient for LT-HSC quiescence through regulation of p21.