Angiogenin Promotes Hematopoietic Regeneration by Dichotomously Regulating Quiescence of Stem and Progenitor Cells

• Published in: Cell Vol. 166; no. 4; pp. 894 - 906
• Main Authors: Goncalves, Kevin A., Silberstein, Lev, Li, Shuping, Severe, Nicolas, Hu, Miaofen G., Yang, Hailing, Scadden, David T., Hu, Guo-fu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.08.2016
• Subjects: Animals; Cell Proliferation; functional properties; Hematopoiesis; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; irradiation; Mice; Mice, Inbred C57BL; Myeloid Cells - metabolism; protein synthesis; Ribonuclease, Pancreatic - metabolism; ribonucleases; ribosomal RNA; RNA, Transfer - metabolism; RNA, Untranslated - metabolism; stem cells; tissues
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2016.06.042

Regulation of stem and progenitor cell populations is critical in the development, maintenance, and regeneration of tissues. Here, we define a novel mechanism by which a niche-secreted RNase, angiogenin (ANG), distinctively alters the functional characteristics of primitive hematopoietic stem/progenitor cells (HSPCs) compared with lineage-committed myeloid-restricted progenitor (MyePro) cells. Specifically, ANG reduces the proliferative capacity of HSPC while simultaneously increasing proliferation of MyePro cells. Mechanistically, ANG induces cell-type-specific RNA-processing events: tRNA-derived stress-induced small RNA (tiRNA) generation in HSPCs and rRNA induction in MyePro cells, leading to respective reduction and increase in protein synthesis. Recombinant ANG protein improves survival of irradiated animals and enhances hematopoietic regeneration of mouse and human HSPCs in transplantation. Thus, ANG plays a non-cell-autonomous role in regulation of hematopoiesis by simultaneously preserving HSPC stemness and promoting MyePro proliferation. These cell-type-specific functions of ANG suggest considerable therapeutic potential. [Display omitted] •HSPC quiescence and progenitor cell proliferation are simultaneously enhanced by ANG•The dichotomous effect of ANG is related to differential RNA processing•ANG prevents and mitigates radiation-induced bone marrow failure•ANG dramatically improves transplantation efficiency of mouse and human HSPCs A new niche-specific modulator maintains the stemness of hematopoetic stem/progenitor cells while promoting the proliferation of myeloid progenitor cells through the regulation of RNA metabolism.