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.
Ayako Nakamura-Ishizu, Desmond Chin, Takayoshi Matsumura, Darren Qiancheng Tan, Makiko Kashio Mochizuki, Deng Jianwen, Toshio Suda