Defining intracellular molecules involved in hematopoietic stem cell (HSC) function is important for future efforts to enhance transplantation. Toward this aim, Chen and colleagues report that Cited2, a transcriptional modifier, is necessary for mouse fetal liver hematopoiesis.
Understanding intracellular events that mediate functions of hematopoietic stem cells (HSCs) is important for realizing improved efficacy of HSC transplantation. In this issue of Blood, Chen and colleagues have advanced this area by demonstrating a new role for Cited2 (cAMP-responsive element–binding protein [CBP]/p300-interacting transactivators with glutamic acid [E] and aspartic acid [D]–rich tail 2)1 in steady-state embryogenesis.
Gene-expression profiling linked Cited2 expression with long-term marrow HSC activity.2 However, the current authors had to study Cited2−/− fetal liver hematopoiesis, since functional deletion of Cited2, a member of a new family of transcriptional modulators, results in embryonic lethality.3 A role for Cited2 in hematopoiesis was shown by the authors in elegant studies demonstrating that Cited2−/− fetal liver was greatly reduced in phenotyped hematopoietic progenitors (HPCs); compromised reconstitution of T- and B-lymphocyte and myeloid cells was apparent after both primary and secondary transplantation of Cited2−/− fetal liver cells, and the competitive repopulating capacity of these HSCs was decreased.
Exactly how Cited2 acts, alone or in combination with other mediators, to regulate normal hematopoiesis is not known. A number of receptor and intracellular signals are reported to modulate HSC and HPC functions.4 These include Notch and Notch ligands, Wnt signaling, HoxB4/PBX1, Bmi-1, C/EBPα, Gfi-1, p21cip1/waf1, p27kip1, PTEN, Nov/CLN3, glycogen synthase kinase-3, ERK1/2- and p38-MAP kinase, ME/ELK4, RAR-γ, Stat3, Stat5, and Mad2. Microarray analysis by Chen and colleagues showed decreased expression of Wnt5a and a panel of myeloid markers in Cited2−/− fetal livers, as well as decreased expression of Bmi-1, Notch, LEF-1, Mcl-1, and GATA-2 in Cited2−/− c-kit+ lineage− fetal liver cells. Placing these molecules into correct positions within interacting networks required to properly mediate self-renewal, proliferation, survival, differentiation, and migration of HSCs—and determining where Cited2 fits into this schema—are vital missing pieces of information. For example, which signals are in linear, branching, or completely separate pipelines, and which occupy key regulatory positions in the cascading sequence of events? Do any of these molecules act as a master switch, and is Cited2 a master regulator? What other roles, if any, does Cited2 play in HSC/HPC function and hematopoiesis? The authors propose future studies involving overexpression of genes identified from the current study in Cited2−/− HSCs, and generation of conditional Cited2 knockout mice at specific development stages and in specific hematopoietic lineages. This should bring us closer to knowing what Cited2 does and does not do.
How HSCs renew themselves is still essentially unknown. While investigators continue to dig away, little by little, at this crucial HSC function, it may be that the field needs to be more creative and think out of the box to get a true picture of the renewal of HSCs, which may not occur as we currently envision it. Whatever model or models are eventually identified for renewal of HSCs, it may be that Cited2 will be an important player in these events. We look forward to finding out.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
