Prolonged maintenance of hematopoietic stem cells that escape from thrombopoietin deprivation
| Autor: | Makiko Mochizuki-Kashio, Deng Jianwen, Toshio Suda, Takayoshi Matsumura, Desmond Wai Loon Chin, Darren Qiancheng Tan, Ayako Nakamura-Ishizu |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Agonist Hematopoiesis and Stem Cells medicine.drug_class Recombinant Fusion Proteins medicine.medical_treatment Immunology Apoptosis Mice Transgenic Receptors Fc Biochemistry Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Cell Self Renewal Receptor Thrombopoietin Mice Knockout Romiplostim Chemistry Cell Cycle hemic and immune systems Cell Biology Hematology Hematopoietic Stem Cells Mitochondria Cell biology Oxidative Stress Haematopoiesis 030104 developmental biology Cytokine Stem cell Energy Metabolism Transcriptome Receptors Thrombopoietin 030217 neurology & neurosurgery Signal Transduction medicine.drug |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. 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 transplantation. Thpofl/fl;AlbCre+/− HSCs exhibited similar stem cell phenotypes but to a lesser degree compared with Thpo−/− HSCs. HSCs that survive Thpo deficiency acquire quiescence in a dose-dependent manner through the modification of their metabolic state. |
| Databáze: | OpenAIRE |
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