1Tokyo women’s medical univeristy, Tokyo, Japan.
2National University of Singapore, Singapore, Singapore.
3Kumamoto Univerisity IRCMS, Japan.
Abstract
Hematopoietic stem cells (HSC) rarely divide, rest in quiescence and proliferate only upon stress hematopoiesis. The cytokine thrombopoietin (Thpo) has been perplexingly described to induce quiescence and promote self-renewal divisions in HSCs. In order to clarify the contradictory effect of Thpo, we conducted a detailed analysis on conventional (Thpo-/-) and liver-specific (Thpofl/fl;AlbCre+/-) Thpo deletion models. Thpo-/- HSCs exhibited profound loss of quiescence, impaired cell cycle progression and increased apoptosis. Thpo-/- HSCs also exhibited diminished mitochondrial mass and impaired mitochondrial bioenergetics. Abnormal HSC phenotypes in Thpo-/- mice were reversible after HSC transplantation into wild type recipients. Moreover, Thpo-/- HSCs acquired quiescence with extended administration of a Thpo-receptor agonist, Romiplostim, and were prone to subsequent stem cell exhaustion during competitive bone marrow (BM) transplantation. Thpofl/fl;AlbCre+/- HSCs exhibited similar stem cell phenotypes but at a lesser extent than Thpo-/- HSCs. HSCs that survive Thpo deficiency acquire quiescence in a dose-dependent manner through the modification of their metabolic state.
Copyright © 2021 American Society of Hematology.
PMID: 33657206 DOI: 10.1182/blood.2020005517