title: Hematopoietic cells from Ube1L-deficient mice exhibit an impaired proliferation defect under the stress of bone marrow transplantation.
abstract: Following bone marrow transplantation, donor stem cells are recruited from their quiescent status to promote the rapid reconstitution in recipients. This dynamic process is tightly regulated by a complex of internal and external signals. Protein modification by the ubiquitin like modifier ISG15 (ISGylation) is strongly induced by type I interferons (IFNs). There are higher levels of type I IFNs and protein ISGylation in the bone marrow of recipients shortly after transplantation. In order to clarify the physiological function of protein ISGylation, we generated a mouse model that lacks protein ISGylation due to deficiency of ISG15 conjugating enzyme Ube1L (Ube1L(-/-)). In this report, we focused on the analysis of the hematopoietic system in Ube1L(-)(/)(-) mice in steady-state hematopoiesis and its potential protective role during bone marrow reconstitution. Here we demonstrated that In Ube1L(-/-) mice, steady-state hematopoiesis was unperturbed. However, transplantation experiment revealed a 50% reduction in repopulation potential of Ube1L-deficient cells at 3weeks posttransplantation, but no differences at 6 and 12weeks. A competitive transplantation experiment magnified and extended this phenotype. Cell cycle analysis revealed that under the condition with high levels of IFNs and protein ISGylation, the Ube1L deficiency can cause G2/M phase block of cell cycle in hematopoietic multipotential progenitors. These observations indicate that although protein ISGylation is dispensable for steady-state hematopoiesis, it plays a significant role during interferon related stress response, such as bone marrow transplantation.
authors.affiliation: Moores UCSD Cancer Center, University of California San Diego, La Jolla, 92093, USA.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Cong
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yin
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002453:Cell Cycle; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics*; D007370:Interferon Type I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044764:Ubiquitin-Activating Enzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D016207:Cytokines; C489550:G1p2 protein, mouse; D007370:Interferon Type I; D014452:Ubiquitins; D007371:Interferon-gamma; D044764:Ubiquitin-Activating Enzymes