title: DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival.
abstract: 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.
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany.|Georg-Speyer-Haus, Frankfurt am Main, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wingert
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany.|Georg-Speyer-Haus, Frankfurt am Main, Germany.
authors.forename: Frederic B
authors.initials: FB
authors.lastname: Thalheimer
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany.|Georg-Speyer-Haus, Frankfurt am Main, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Haetscher
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany.|Georg-Speyer-Haus, Frankfurt am Main, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Rehage
authors.affiliation: Department of Biosystems Science and Engineering (D-BSSE), ETH Zurich, Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: LOEWE Center for Cell and Gene Therapy and Department of Medicine, Hematology/Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany.|Georg-Speyer-Haus, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins
keywords: Cell fate decisions; Differentiation; GADD45 family; Hematopoietic stem cells; In vivo transplantations; Self-renewal; Single cell tracking