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Stem Cell Regulation and Host Defense: The Logic and the Paradox

2008; Elsevier BV; Volume: 2; Issue: 1 Linguagem: Inglês

10.1016/j.stem.2007.12.002

1934-5909

Göran Karlsson, Stefan Karlsson,

Phagocytosis and Immune Regulation

As a response against serious infection, there is often a need to produce more leukocytes to defend the organism against the infectious agent. In this issue of Cell Stem Cell, Goodell and colleagues (Feng et al., 2008Feng C.G. Weksberg D.C. Taylor G.A. Sher A. Goodell M.A. Cell Stem Cell. 2008; 2 (this issue): 83-89Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar) find a link between regulators of host defense and hematopoietic stem cells. As a response against serious infection, there is often a need to produce more leukocytes to defend the organism against the infectious agent. In this issue of Cell Stem Cell, Goodell and colleagues (Feng et al., 2008Feng C.G. Weksberg D.C. Taylor G.A. Sher A. Goodell M.A. Cell Stem Cell. 2008; 2 (this issue): 83-89Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar) find a link between regulators of host defense and hematopoietic stem cells. Even though hematopoietic stem cells (HSCs) in steady state are predominantly inactive and quiescent, they possess an enormous potential to proliferate and expand. Although bone marrow (BM) transplantation protocols have taken advantage of this proliferative capacity for decades, little is known about the use for this potential during more physiological conditions of hematopoietic stress. However, recent studies have demonstrated that increased proliferation and altered hematopoietic differentiation can be induced as part of the immune response to infectious disease (Nagai et al., 2006Nagai Y. Garrett K.P. Ohta S. Bahrun U. Kouro T. Akira S. Takatsu K. Kincade P.W. Immunity. 2006; 24: 801-812Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar). Intriguingly, the discovery of Toll-like receptor expression in HSCs suggests that this activation, which probably serves to replenish the effector cells, seems to be a direct early event in the innate host defense (Nagai et al., 2006Nagai Y. Garrett K.P. Ohta S. Bahrun U. Kouro T. Akira S. Takatsu K. Kincade P.W. Immunity. 2006; 24: 801-812Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar). In this issue of Cell Stem Cell, Feng et al., 2008Feng C.G. Weksberg D.C. Taylor G.A. Sher A. Goodell M.A. Cell Stem Cell. 2008; 2 (this issue): 83-89Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar support these findings and provide a genetic link between immune system signaling and in vivo function of HSCs. The p47 GTPases, also referred to as immunity-related GTPases, have been characterized as interferon-responsive effectors of the immune system. One of these GTPases, Lrg-47, is required for host defense against many intracellular pathogens, demonstrated by impaired intracellular microbial killing ability by Lrg-47−/− mice (MacMicking et al., 2003MacMicking J.D. Taylor G.A. McKinney J.D. Science. 2003; 302: 654-659Crossref PubMed Scopus (525) Google Scholar). Upon infection with several pathogens, Lrg-47−/− mice fail to control the infection and develop pancytopenia prior to death (Feng et al., 2004Feng C.G. Collazo-Custodio C.M. Eckhaus M. Hieny S. Belkaid Y. Elkins K. Jankovic D. Taylor G.A. Sher A. J. Immunol. 2004; 172: 1163-1168Crossref PubMed Scopus (101) Google Scholar). Recently, Venezia et al., 2004Venezia T.A. Merchant A.A. Ramos C.A. Whitehouse N.L. Young A.S. Shaw C.A. Goodell M.A. PLoS Biol. 2004; 2: e301https://doi.org/10.1371/journal.pbio.0020301Crossref PubMed Scopus (259) Google Scholar studied gene expression profiles in proliferating and quiescent HSCs and identified Lrg-47 as a potential HSC regulatory gene (Venezia et al., 2004Venezia T.A. Merchant A.A. Ramos C.A. Whitehouse N.L. Young A.S. Shaw C.A. Goodell M.A. PLoS Biol. 2004; 2: e301https://doi.org/10.1371/journal.pbio.0020301Crossref PubMed Scopus (259) Google Scholar). Because Lrg-47 was upregulated in HSCs after hematopoietic stress and profound hematopoietic defects have been observed after infectious challenge in Lrg-47−/− mice, Feng et al., 2008Feng C.G. Weksberg D.C. Taylor G.A. Sher A. Goodell M.A. Cell Stem Cell. 2008; 2 (this issue): 83-89Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar hypothesized that Lrg-47 might be an HSC regulator after disturbance of hematopoietic homeostasis. In their present paper, they indeed report delayed hematopoietic recovery after 5-fluorouracil (5FU) myeloablation of Lrg-47−/− mice, supporting earlier observations describing an upregulation of Lrg-47 1 day after this treatment (Venezia et al., 2004Venezia T.A. Merchant A.A. Ramos C.A. Whitehouse N.L. Young A.S. Shaw C.A. Goodell M.A. PLoS Biol. 2004; 2: e301https://doi.org/10.1371/journal.pbio.0020301Crossref PubMed Scopus (259) Google Scholar). Because this chemotherapeutic agent selectively kills dividing cells, causing an activation response of the quiescent HSCs to replenish the hematopoietic system, these findings indicate that the proliferative response to hemaopoietic stress by Lrg-47−/− HSCs is impaired. A profound repopulation defect was also detected in Lrg-47−/− HSCs because a robust engraftment was not seen when a 25-fold excess of knockout BM cells was used to compete with normal control marrow in a competitive repopulation experiment. The percentage of Lin-Sca1+c-kit+ progenitor and stem cells was similar in Lrg-47−/− and normal HSCs, so the repopulation deficiency is mostly a functional deficiency and cannot be explained by a reduction of HSCs. Additionally, data are presented indicating that Lrg-47 may regulate apoptotic pathways, because 5FU-treated Lrg-47-deficient HSCs exhibited increased apoptosis. Thus, it seems like Lrg-47 has a critical role in boosting HSC proliferation and protecting the HSC pool when the hematopoietic system needs to be replenished. Intriguingly, these effects proved absolutely critical for normal immune function. After infection with M. Avium, there was no expansion of Lrg-47−/− Lin-Sca1+c-kit+ progenitor and stem cells, whereas this population in wild-type (WT) mice was amplified 15-fold. Similarly, there was a substantial reduction of functional CFCs after infection compared to WT animals. The results are logical in one sense. A gene that regulates successful response to infection may also be involved in regulating production of more leukocytes by stimulating a reaction at the HSC level of the hematopoietic hierarchy to produce more white cells for active defense against microorganisms. However, the presented data are also somewhat paradoxical. Contrary to the delay in proliferative response and impaired reconstitution capacity observed after hematopoietic stress, steady-state Lrg-47−/− HSCs are hyperproliferative, as measured by BrdU incorporation of dividing cells. Accordingly, there was a substantially increased loss of HSC-enriched side population cells upon 5FU treatment of Lrg-47−/− mice. Based on these data, the authors present a hypothesis that Lrg-47 may be a regulator that keeps HSCs quiescent. Thus, the findings by Feng et al., 2008Feng C.G. Weksberg D.C. Taylor G.A. Sher A. Goodell M.A. Cell Stem Cell. 2008; 2 (this issue): 83-89Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar suggest that Lrg-47 has multiple roles in governing HSC fate. In steady state, it protects the HSCs by maintaining quiescence. During situations of hematopoietic stress, Lrg-47 instead boosts proliferation as well as restrains cell death, resulting in an expansion of HSCs when the hematopoietic system is in need of replenishment. Additionally, the study implicates Lrg-47 as a genetic link between the immune system and HSCs and demonstrates that an expansion of hematopoietic progenitor and stem cells is an early, thus possibly direct, event in the immune response to infectious disease. So how can a molecule that is important for maintaining HSC quiescence be critical for HSC expansion after hematopoietic stress at the same time? On the molecular level, it is not known how Lrg-47 acts to regulate HSCs and it will be of great interest to follow future studies regarding the mechanisms behind its multiple roles in HSC function. However, the hyperproliferation of hematopoietic progenitors observed in Lrg-47 mice could possibly lead to an exhaustion of the HSC pool and impaired reconstitution capacity. This could be linked with earlier findings demonstrating that Lrg-47 may regulate cytoskeletal changes or cell motility (Kaiser et al., 2004Kaiser F. Kaufmann S.H. Zerrahn J. J. Cell Sci. 2004; 117: 1747-1756Crossref PubMed Scopus (27) Google Scholar). This hypothesis fits well with the growing evidence implicating the physical location of HSCs within the endosteal stem cell niche to play a strong role in regulating the proliferation of HSCs (Wilson and Trumpp, 2006Wilson A. Trumpp A. Nat. Rev. Immunol. 2006; 6: 93-106Crossref PubMed Scopus (1003) Google Scholar) (Figure 1). It may therefore be possible that Lrg-47 does not directly regulate quiescence or proliferation but is rather involved in HSC lodging to and migration from the stem cell niche and thereby affect the stem cell properties or “stemness” of HSCs. Nevertheless, the intriguing work by Feng et al., 2008Feng C.G. Weksberg D.C. Taylor G.A. Sher A. Goodell M.A. Cell Stem Cell. 2008; 2 (this issue): 83-89Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar will undoubtedly increase the interest for the connection between HSC function and the immune response to infectious disease. Wnt, Activin, and BMP Signaling Regulate Distinct Stages in the Developmental Pathway from Embryonic Stem Cells to BloodNostro et al.Cell Stem CellJanuary 10, 2008In BriefThe embryonic stem cell differentiation system was used to define the roles of the Activin/Nodal, BMP, and canonical Wnt signaling pathways at three distinct developmental stages during hematopoietic ontogeny: induction of a primitive streak-like population, formation of Flk1+ mesoderm, and induction of hematopoietic progenitors. Activin/Nodal and Wnt, but not BMP, signaling are required for the induction of the primitive streak. Although BMP is not required for primitive streak induction, it displays a strong posteriorizing effect on this population. Full-Text PDF Open Archive