Zfx: At the Crossroads of Survival and Self-Renewal
2007; Cell Press; Volume: 129; Issue: 2 Linguagem: Inglês
10.1016/j.cell.2007.04.002
ISSN1097-4172
Autores Tópico(s)Leadership, Courage, and Heroism Studies
ResumoAs the molecular mechanisms that govern stem cell fate are beginning to be unraveled, Galan-Caridad et al., 2007Galan-Caridad J.M. Harel S. Arenzana T.L. Hou Z.E. Doetsch F.K. Mirny L.A. Reizis B. Cell. 2007; (this issue)PubMed Google Scholar report in this issue of Cell a common role for the transcription factor Zfx in the self-renewal/maintenance of both embryonic stem cells and hematopoietic stem cells. Their work suggests that a regulator of self-renewal can be shared between two different cell types. As the molecular mechanisms that govern stem cell fate are beginning to be unraveled, Galan-Caridad et al., 2007Galan-Caridad J.M. Harel S. Arenzana T.L. Hou Z.E. Doetsch F.K. Mirny L.A. Reizis B. Cell. 2007; (this issue)PubMed Google Scholar report in this issue of Cell a common role for the transcription factor Zfx in the self-renewal/maintenance of both embryonic stem cells and hematopoietic stem cells. Their work suggests that a regulator of self-renewal can be shared between two different cell types. A key defining feature of stem cells is their ability to self-renew, that is, to preserve the identity of a parental cell through cell division in at least one of the two daughter cells. In general, the requirements for self-renewal include inhibition of differentiation with concomitant suppression of apoptosis and senescence pathways (Figure 1). Only under these circumstances does self-renewal occur, irrespective of stem cell type or the master fate regulators involved. In this issue of Cell, Galan-Caridad et al., 2007Galan-Caridad J.M. Harel S. Arenzana T.L. Hou Z.E. Doetsch F.K. Mirny L.A. Reizis B. Cell. 2007; (this issue)PubMed Google Scholar examined the self-renewal potential of murine embryonic stem cells (ESC) and tissue hematopoietic stem cells (HSC), two distinct types of stem cells that differ in several respects. First, ESC are derived from the inner cell mass of the early mammalian embryo and although only transient in vivo, they can be maintained in vitro as cell lines by the addition of serum (as a source of bone morphogenetic proteins) and leukemia inhibitory factor to the culture medium. HSC are specified in the aorta-gonad-mesonephros/yolk sac and then migrate to the fetal liver where they undergo expansion (from embryonic day 11.5–16.5). They ultimately migrate to the bone marrow niche (from embryonic day 17.5 onward) where they persist throughout adulthood, mostly in the G0 phase of the cell cycle (Figure 1). Attempts to maintain or expand HSC outside of their in vivo niche remain modest, and HSC cell lines are not available currently. Second, ESC are pluripotent, that is, they can differentiate into all cell types of an adult animal; in contrast, HSC are multipotent, only giving rise to blood cell lineages. Third, quiescence and senescence are observed in HSC but not in ESC. Finally, ESC undergo symmetrical self-renewal divisions, with one stem cell giving rise to two daughter stem cells, resulting in an expansion in stem cell numbers. In contrast, adult HSC predominantly undergo asymmetrical self-renewal divisions, generating one stem cell and one more committed cell, thus preserving stem cell numbers while enabling blood cell regeneration in vivo. HSC undergo symmetrical self-renewal divisions only in specific and temporally restricted developmental contexts. Although key master regulators of HSC cell fate are still poorly defined, the molecular basis of ESC self-renewal are more rapidly unfolding, with recent evidence suggesting the involvement of two distinct groups of genes, Nanog/Oct4/Sox2 and Tbx3/Tcl1/Esrrb/Dppa4 (Ivanova et al., 2006Ivanova N. Dobrin R. Lu R. Kotenko I. Levorse J. DeCoste C. Schafer X. Lun Y. Lemischka I.R. Nature. 2006; 442: 533-538Crossref PubMed Scopus (764) Google Scholar), in the regulation of two separate pathways. Given the differences between ESC and HSC, the question arises whether there are commonalities in the molecular mechanisms governing their self-renewal. In this issue, Galan-Caridad et al., 2007Galan-Caridad J.M. Harel S. Arenzana T.L. Hou Z.E. Doetsch F.K. Mirny L.A. Reizis B. Cell. 2007; (this issue)PubMed Google Scholar now describe a role for the zinc finger transcription factor Zfx in sustaining self-renewal divisions in both ESC and HSC. Given that Zfx knockout mice die at the neonatal stage, the authors generated a conditional Zfx allele in ESC to enable deletion of this gene in ESC and HSC at specific time points. Loss of Zfx in ESC resulted in near depletion of these cells in culture after only two to three passages, pointing to a proliferation defect with an accompanying increase in apoptosis that became very pronounced in serum-free conditions. Despite their rapid exhaustion in vitro, they still harbored markers of undifferentiated cells. Interestingly, Zfx-deficient ESC contributed to the majority of tissues in chimeric animals, excluding hematopoietic tissues, and could form teratomas upon subcutaneous injection into mice. These data suggest that Zfx normally suppresses apoptosis in ESC maintained in culture conditions that favor their self-renewal, but seems dispensable for their differentiation. In the hematopoietic system, adult mice lacking Zfx exhibited a steep decline in phenotypically defined HSC as early as 2–5 weeks postexcision of the allele, but their progeny transiently sustained blood cell formation. Clearly, self-renewal and maintenance of the long-term repopulating HSC is compromised in this setting, as explained by a moderate increase in apoptosis. Loss of the Zfx gene in the hematopoietic system of early embryos resulted in a more modest decrease in phenotypically defined fetal liver HSC, suggesting that Zfx is not required for this stage of development. In competitive adoptive HSC transfer experiments, Zfx-deficient stem cells displayed multilineage differentiation prior to depletion, but contribution of Zfx null cells to recipient peripheral blood reconstitution gradually declined over a 2–6 month period. The authors demonstrated that stem cell homing to the bone marrow was not affected, and seeding of the Zfx-deficient HSC into another niche, such as the spleen, was not found. This study depicts fascinating aspects of HSC biology. To begin, it underscores the importance of following HSC behavior over time, to detect the onset of phenotypic aberrations, and thus attempt to decipher the underlying molecular dysfunction. Indeed, apoptosis may be maximal at the precise time point when HSC numbers begin to decline, and the reported difference in death rates between normal and Zfx null HSC could have been missed if cells were analyzed at a later time point. In addition, it provides an incentive to analyze data in light of cell-cycle phase distributions. For example, defects that would force HSC into apoptosis from G0 may not directly involve self-renewal determinants, because by definition, self-renewal implies cell-cycle entry (Figure 1). Moreover, it must be remembered that some HSC properties, such as their ability to engraft, vary according to cell-cycle phase. In the future, it would also be interesting to determine if Zfx regulates HSC senescence. Moreover, it is tempting to draw a parallel between Zfx and other transcription factors that regulate HSC self-renewal such as Gfi1, Bmi1, Etv6, and FoxO (Hock et al., 2004aHock H. Hamblen M.J. Rooke H.M. Schindler J.W. Saleque S. Fujiwara Y. Orkin S.H. Nature. 2004; 431: 1002-1007Crossref PubMed Scopus (406) Google Scholar, Hock et al., 2004bHock H. Meade E. Medeiros S. Schindler J.W. Valk P.J. Fujiwara Y. Orkin S.H. Genes Dev. 2004; 18: 2336-2341Crossref PubMed Scopus (187) Google Scholar, Lessard and Sauvageau, 2003Lessard J. Sauvageau G. Nature. 2003; 423: 255-260Crossref PubMed Scopus (1244) Google Scholar, Park et al., 2003Park I.K. Qian D. Kiel M. Becker M.W. Pihalja M. Weissman I.L. Morrison S.J. Clarke M.F. Nature. 2003; 423: 302-305Crossref PubMed Scopus (1540) Google Scholar, Tothova et al., 2007Tothova Z. Kollipara R. Huntly B.J. Lee B.H. Castrillon D.H. Cullen D.E. McDowell E.P. Lazo-Kallanian S. Williams I.R. Sears C. et al.Cell. 2007; 128: 325-339Abstract Full Text Full Text PDF PubMed Scopus (1166) Google Scholar). After establishing that Zfx is important for the self-renewal of ESC and HSC, Galan-Caridad et al., 2007Galan-Caridad J.M. Harel S. Arenzana T.L. Hou Z.E. Doetsch F.K. Mirny L.A. Reizis B. Cell. 2007; (this issue)PubMed Google Scholar investigated the underlying molecular circuits of Zfx in these two stem cell populations. Analysis of gene expression using microarrays revealed a common set of five downregulated and 20 upregulated Zfx target genes in ESC and HSC. Chromatin immunoprecipitation (ChIP) studies suggested that three of the downregulated genes are direct targets of Zfx and that their mRNA levels increased upon Zfx reintroduction. The authors examined additional candidate genes in Zfx-deficient ESC and observed that the master regulators of ESC pluripotency Nanog/Oct4/Sox2 were only minimally affected by the removal of Zfx, whereas other ESC-specific genes such as Ceacam1, Dub, Tbx3, and Tcl1 were all downregulated. ChIP assays further demonstrated that Tbx3 and Tcl1 are direct targets of Zfx. Interestingly, Tbx3 has been previously described to suppress apoptosis (Carlson et al., 2002Carlson H. Ota S. Song Y. Chen Y. Hurlin P.J. Oncogene. 2002; 21: 3827-3835Crossref PubMed Scopus (81) Google Scholar), and downregulation of Tbx3 in Zfx null stem cells could provide an explanation for their increased cell death. Of note, a recent report suggests that Nanog does not regulate self-renewal in HSC (Tanaka et al., 2007Tanaka Y. Era T. Nishikawa S.I. Kawamata S. Blood. 2007; (in Press. Published online March 14, 2007)https://doi.org/10.1182/blood.2006.08.039628Crossref Google Scholar). The new work by Galan-Caridad et al., 2007Galan-Caridad J.M. Harel S. Arenzana T.L. Hou Z.E. Doetsch F.K. Mirny L.A. Reizis B. Cell. 2007; (this issue)PubMed Google Scholar sheds light on the dual dependence of both pluripotent and multipotent stem cells on the transcription factor Zfx for their maintenance. It also brings us to the intersecting paths of self-renewal and cell survival. Indeed, the direct comparison of ESC and HSC self-renewal and survival programs will require a more complete characterization of their respective components. Zfx Controls the Self-Renewal of Embryonic and Hematopoietic Stem CellsGalan-Caridad et al.CellApril 20, 2007In BriefStem cells (SC) exhibit a unique capacity for self-renewal in an undifferentiated state. It is unclear whether the self-renewal of pluripotent embryonic SC (ESC) and of tissue-specific adult SC such as hematopoietic SC (HSC) is controlled by common mechanisms. The deletion of transcription factor Zfx impaired the self-renewal but not the differentiation capacity of murine ESC; conversely, Zfx overexpression facilitated ESC self-renewal by opposing differentiation. Furthermore, Zfx deletion abolished the maintenance of adult HSC but did not affect erythromyeloid progenitors or fetal HSC. Full-Text PDF Open Archive
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