DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival
| العنوان: | DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival |
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| المؤلفون: | Frederic B. Thalheimer, Susanne Wingert, Maike Rehage, Nadine Haetscher, Michael A. Rieger, Timm Schroeder |
| المصدر: | Stem Cells (Dayton, Ohio) |
| بيانات النشر: | John Wiley and Sons Inc., 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Cell cycle checkpoint, Cell Survival, Cellular differentiation, Cell fate decisions, Apoptosis, Cell Cycle Proteins, Biology, p38 Mitogen-Activated Protein Kinases, Tissue‐Specific Stem Cells, Blood cell, 03 medical and health sciences, Mice, Single cell tracking, medicine, Animals, Humans, Progenitor cell, Cell Proliferation, Cell growth, Gene Expression Regulation, Developmental, Nuclear Proteins, Cell Differentiation, Cell Biology, Cell Cycle Checkpoints, Cell cycle, Self‐renewal, Hematopoietic Stem Cells, Cell biology, Hematopoiesis, Haematopoiesis, 030104 developmental biology, medicine.anatomical_structure, Differentiation, GADD45 family, Molecular Medicine, Stem cell, Developmental Biology, In vivo transplantations, DNA Damage, Signal Transduction |
| الوصف: | Hematopoietic stem cells (HSCs) maintain blood cell production life-long by their unique abilities of self-renewal and differentiation into all blood cell lineages. Growth arrest and DNA-damage-inducible 45 alpha (GADD45A) is induced by genotoxic stress in HSCs. GADD45A has been implicated in cell cycle control, cell death and senescence, as well as in DNA-damage repair. In general, GADD45A provides cellular stability by either arresting the cell cycle progression until DNA damage is repaired or, in cases of fatal damage, by inducing apoptosis. However, the function of GADD45A in hematopoiesis remains controversial. We revealed the changes in murine HSC fate control orchestrated by the expression of GADD45A at single cell resolution. In contrast to other cellular systems, GADD45A expression did not cause a cell cycle arrest or an alteration in the decision between cell survival and apoptosis in HSCs. Strikingly, GADD45A strongly induced and accelerated the differentiation program in HSCs. Continuous tracking of individual HSCs and their progeny via time-lapse microscopy elucidated that once GADD45A was expressed, HSCs differentiate into committed progenitors within 29 hours. GADD45A-expressing HSCs failed to long-term reconstitute the blood of recipients by inducing multilineage differentiation in vivo. Importantly, γ-irradiation of HSCs induced their differentiation by upregulating endogenous GADD45A. The differentiation induction by GADD45A was transmitted by activating p38 Mitogen-activated protein kinase (MAPK) signaling and allowed the generation of megakaryocytic-erythroid, myeloid, and lymphoid lineages. These data indicate that genotoxic stress-induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system. |
| اللغة: | English |
| تدمد: | 1549-4918 1066-5099 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1f669a4e38bbe35c258a4f3510267dacTest http://europepmc.org/articles/PMC4832267Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1f669a4e38bbe35c258a4f3510267dac |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15494918 10665099 |
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