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Ontogeny of Tissue-Resident Macrophages.

Hoeffel G, Ginhoux F - Front Immunol (2015)

Bottom Line: The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently.These tissue-resident macrophages derive from sequential seeding of tissues by two precursors during embryonic development.Thus, hematopoietic stem cell-independent embryonic precursors transiently present in the YS and the FL give rise to long-lasting self-renewing macrophage populations.

View Article: PubMed Central - PubMed

Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR) , Singapore , Singapore.

ABSTRACT
The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. Originally described as part of the mononuclear phagocyte system, macrophages were long thought to derive solely from adult blood circulating monocytes. However, accumulating evidence now shows that certain macrophage populations are in fact independent from monocyte and even from adult bone marrow hematopoiesis. These tissue-resident macrophages derive from sequential seeding of tissues by two precursors during embryonic development. Primitive macrophages generated in the yolk sac (YS) from early erythro-myeloid progenitors (EMPs), independently of the transcription factor c-Myb and bypassing monocytic intermediates, first give rise to microglia. Later, fetal monocytes, generated from c-Myb(+) EMPs that initially seed the fetal liver (FL), then give rise to the majority of other adult macrophages. Thus, hematopoietic stem cell-independent embryonic precursors transiently present in the YS and the FL give rise to long-lasting self-renewing macrophage populations.

No MeSH data available.


Related in: MedlinePlus

Fate-mapping systems. (A) The Runx-iCre fate-mapping model (86) used in our study targets the hemogenic transition (88), hence, labeling specifically progenitors in the process of budding out from the hemogenic endothelium. The Runx1 expression decreases in progenitors once they start to express Vav thus reducing the chances of tagging released progenitors from precedent waves (88). As a consequence, Runx-iCre tagging is restricted to a short time window in the lifespan of a given progenitor and allows a sharp definition of each hematopoietic wave. However, this model also restricts the tagging to only a small fraction of the targeted progenitor wave. (B) Tie2 is expressed in all endothelial cells that constitute the hemogenic endothelia even before the hemogenic transition (89). Thus, all endothelial cells and their progeny (non-hematopoietic and hematopoietic cells) will be labeled after tamoxifen injection using the Tie2-iCre model. As a consequence, an early tamoxifen injection (such as at E7.5) will result in the tagging of all hematopoietic cells emerging before the time of analysis. This will include progenitors from the primitive, the transient definitive, and the definitive waves if, for example, the analysis is done at E11.5. A late injection (such as at E10.5) will restrict the tagging to only the latest hematopoietic stem cells wave as they are just budding from HEs (90). Thus, this model might not be suitable to clearly separate the primitive from the transient definitive waves of hematopoiesis. However, this model could be important to study late HSC progeny as no other progenitors than HSCs emerge from HE after E10.5 (91). (C) C-kit is expressed by all hematopoietic progenitors and does not label endothelial cells that constitute the HEs (89). An early tamoxifen injection (such as at E7.5) will restrict the labeling to early progenitors making suitable the c-kit-iCre model to study the primitive hematopoiesis. However, the FL recruits progenitors of each hematopoietic wave from E8.5 until E11 (79). These progenitors still express c-kit and coexist after seeding the FL during the time necessary for their differentiation (47, 55). A later tamoxifen injection (such as at E9.5) might thus result in the cumulative labeling of undifferentiated primitive and definitive progenitors, including the transient wave of EMPs and LMPs. Thus, such model may not be suitable to resolve the complexity of the different embryonic hematopoietic waves characterized by short time windows of emergence and strong overlapping tendencies. Primitive hematopoietic progenitors are rapidly consumed and the engagement of EMPs and LMPs in FL hematopoiesis reduces the expression of c-kit on their surface. Thus, later tamoxifen injection (such as at E11.5) could restrict the labeling to newly derived HSCs expressing high level of c-kit without labeling precedent progenitor waves (87). Such model might be interesting to study the progeny of late HSCs although the risk of tagging the progeny of EMPs and LMPs or later committed progenitors derived from HSCs remains high and difficult to exclude. Further analysis would be necessary to clarify the potential of such model.
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Figure 6: Fate-mapping systems. (A) The Runx-iCre fate-mapping model (86) used in our study targets the hemogenic transition (88), hence, labeling specifically progenitors in the process of budding out from the hemogenic endothelium. The Runx1 expression decreases in progenitors once they start to express Vav thus reducing the chances of tagging released progenitors from precedent waves (88). As a consequence, Runx-iCre tagging is restricted to a short time window in the lifespan of a given progenitor and allows a sharp definition of each hematopoietic wave. However, this model also restricts the tagging to only a small fraction of the targeted progenitor wave. (B) Tie2 is expressed in all endothelial cells that constitute the hemogenic endothelia even before the hemogenic transition (89). Thus, all endothelial cells and their progeny (non-hematopoietic and hematopoietic cells) will be labeled after tamoxifen injection using the Tie2-iCre model. As a consequence, an early tamoxifen injection (such as at E7.5) will result in the tagging of all hematopoietic cells emerging before the time of analysis. This will include progenitors from the primitive, the transient definitive, and the definitive waves if, for example, the analysis is done at E11.5. A late injection (such as at E10.5) will restrict the tagging to only the latest hematopoietic stem cells wave as they are just budding from HEs (90). Thus, this model might not be suitable to clearly separate the primitive from the transient definitive waves of hematopoiesis. However, this model could be important to study late HSC progeny as no other progenitors than HSCs emerge from HE after E10.5 (91). (C) C-kit is expressed by all hematopoietic progenitors and does not label endothelial cells that constitute the HEs (89). An early tamoxifen injection (such as at E7.5) will restrict the labeling to early progenitors making suitable the c-kit-iCre model to study the primitive hematopoiesis. However, the FL recruits progenitors of each hematopoietic wave from E8.5 until E11 (79). These progenitors still express c-kit and coexist after seeding the FL during the time necessary for their differentiation (47, 55). A later tamoxifen injection (such as at E9.5) might thus result in the cumulative labeling of undifferentiated primitive and definitive progenitors, including the transient wave of EMPs and LMPs. Thus, such model may not be suitable to resolve the complexity of the different embryonic hematopoietic waves characterized by short time windows of emergence and strong overlapping tendencies. Primitive hematopoietic progenitors are rapidly consumed and the engagement of EMPs and LMPs in FL hematopoiesis reduces the expression of c-kit on their surface. Thus, later tamoxifen injection (such as at E11.5) could restrict the labeling to newly derived HSCs expressing high level of c-kit without labeling precedent progenitor waves (87). Such model might be interesting to study the progeny of late HSCs although the risk of tagging the progeny of EMPs and LMPs or later committed progenitors derived from HSCs remains high and difficult to exclude. Further analysis would be necessary to clarify the potential of such model.

Mentions: The contribution of HSCs to FL hematopoiesis is complex to evaluate, partly because of the lack of specific fate-mapping models, and also the relatively limited knowledge regarding embryonic HSC maintenance and homeostasis in this environment. The capacity for long-term reconstitution, which defines functional HSCs, is present in the AGM by E10.5 (76). However, lineage-specific commitment may not occur in vivo immediately after reaching the FL environment. A number of other progenitors generated during transient definitive hematopoiesis, as discussed above, are already present and able to give rise to almost all cell lineages, which could prevent HSC consumption and differentiation (Figure 5). Evaluation of HSC contribution has long been based on the assumption that all hematopoietic cells in the FL were derived from HSCs as is the case in the BM (81). Many multipotential progenitors share the same phenotype with pre-HSC and HSCs, such as the expression of CD41 and AA4.1 (60), adding to this confusion. The combination of the marker Sca-1 and new markers such as those from the SLAM family (82) have greatly helped to clarify the characterization of HSCs, defined now as Lin−ckit+Sca-1+CD150+CD48−CD244−. However, no specific fate-mapping model exists to characterize embryonic HSC progeny with the exception of the Flt3-Cre model (83), which was used until now with the assumption that embryonic and adult HSCs follow similar differentiation pathways. Our recent report suggests that the Flt3-Cre model can also be used to follow the progeny of LMPs (15). Furthermore, in the nascent BM, the long-term repopulation (LTR) capacity that characterizes functional HSCs is only observed at around E17.5 (84). Considering the time required to initiate full HSC differentiation, these data suggest that proper adult HSC-derived hematopoiesis does not take place in the BM until a few days after birth. Characterization of the functional specificities and regulatory pathways of HE that give rise to HSCs versus those that generate EMPs and other multipotential progenitors could aid the development of new fate-mapping models and improve our understanding of this process (85). Use of other fate-mapping models such as the Runx1-Mer-Cre-Mer (Runx1-iCre) (86), Tie2-Mer-Cre-Mer mice (14), and the c-kit-Mer-Cre-Mer mice (87) provided complementary results, although a careful analysis of the targeted cells in time and space is not yet fully available for the last two models. We present here our best interpretation of the data provided in these two recent studies that have used these models in light of the literature and our own results and experience using the Runx1-iCre model (Figure 6).


Ontogeny of Tissue-Resident Macrophages.

Hoeffel G, Ginhoux F - Front Immunol (2015)

Fate-mapping systems. (A) The Runx-iCre fate-mapping model (86) used in our study targets the hemogenic transition (88), hence, labeling specifically progenitors in the process of budding out from the hemogenic endothelium. The Runx1 expression decreases in progenitors once they start to express Vav thus reducing the chances of tagging released progenitors from precedent waves (88). As a consequence, Runx-iCre tagging is restricted to a short time window in the lifespan of a given progenitor and allows a sharp definition of each hematopoietic wave. However, this model also restricts the tagging to only a small fraction of the targeted progenitor wave. (B) Tie2 is expressed in all endothelial cells that constitute the hemogenic endothelia even before the hemogenic transition (89). Thus, all endothelial cells and their progeny (non-hematopoietic and hematopoietic cells) will be labeled after tamoxifen injection using the Tie2-iCre model. As a consequence, an early tamoxifen injection (such as at E7.5) will result in the tagging of all hematopoietic cells emerging before the time of analysis. This will include progenitors from the primitive, the transient definitive, and the definitive waves if, for example, the analysis is done at E11.5. A late injection (such as at E10.5) will restrict the tagging to only the latest hematopoietic stem cells wave as they are just budding from HEs (90). Thus, this model might not be suitable to clearly separate the primitive from the transient definitive waves of hematopoiesis. However, this model could be important to study late HSC progeny as no other progenitors than HSCs emerge from HE after E10.5 (91). (C) C-kit is expressed by all hematopoietic progenitors and does not label endothelial cells that constitute the HEs (89). An early tamoxifen injection (such as at E7.5) will restrict the labeling to early progenitors making suitable the c-kit-iCre model to study the primitive hematopoiesis. However, the FL recruits progenitors of each hematopoietic wave from E8.5 until E11 (79). These progenitors still express c-kit and coexist after seeding the FL during the time necessary for their differentiation (47, 55). A later tamoxifen injection (such as at E9.5) might thus result in the cumulative labeling of undifferentiated primitive and definitive progenitors, including the transient wave of EMPs and LMPs. Thus, such model may not be suitable to resolve the complexity of the different embryonic hematopoietic waves characterized by short time windows of emergence and strong overlapping tendencies. Primitive hematopoietic progenitors are rapidly consumed and the engagement of EMPs and LMPs in FL hematopoiesis reduces the expression of c-kit on their surface. Thus, later tamoxifen injection (such as at E11.5) could restrict the labeling to newly derived HSCs expressing high level of c-kit without labeling precedent progenitor waves (87). Such model might be interesting to study the progeny of late HSCs although the risk of tagging the progeny of EMPs and LMPs or later committed progenitors derived from HSCs remains high and difficult to exclude. Further analysis would be necessary to clarify the potential of such model.
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Related In: Results  -  Collection

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Show All Figures
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Figure 6: Fate-mapping systems. (A) The Runx-iCre fate-mapping model (86) used in our study targets the hemogenic transition (88), hence, labeling specifically progenitors in the process of budding out from the hemogenic endothelium. The Runx1 expression decreases in progenitors once they start to express Vav thus reducing the chances of tagging released progenitors from precedent waves (88). As a consequence, Runx-iCre tagging is restricted to a short time window in the lifespan of a given progenitor and allows a sharp definition of each hematopoietic wave. However, this model also restricts the tagging to only a small fraction of the targeted progenitor wave. (B) Tie2 is expressed in all endothelial cells that constitute the hemogenic endothelia even before the hemogenic transition (89). Thus, all endothelial cells and their progeny (non-hematopoietic and hematopoietic cells) will be labeled after tamoxifen injection using the Tie2-iCre model. As a consequence, an early tamoxifen injection (such as at E7.5) will result in the tagging of all hematopoietic cells emerging before the time of analysis. This will include progenitors from the primitive, the transient definitive, and the definitive waves if, for example, the analysis is done at E11.5. A late injection (such as at E10.5) will restrict the tagging to only the latest hematopoietic stem cells wave as they are just budding from HEs (90). Thus, this model might not be suitable to clearly separate the primitive from the transient definitive waves of hematopoiesis. However, this model could be important to study late HSC progeny as no other progenitors than HSCs emerge from HE after E10.5 (91). (C) C-kit is expressed by all hematopoietic progenitors and does not label endothelial cells that constitute the HEs (89). An early tamoxifen injection (such as at E7.5) will restrict the labeling to early progenitors making suitable the c-kit-iCre model to study the primitive hematopoiesis. However, the FL recruits progenitors of each hematopoietic wave from E8.5 until E11 (79). These progenitors still express c-kit and coexist after seeding the FL during the time necessary for their differentiation (47, 55). A later tamoxifen injection (such as at E9.5) might thus result in the cumulative labeling of undifferentiated primitive and definitive progenitors, including the transient wave of EMPs and LMPs. Thus, such model may not be suitable to resolve the complexity of the different embryonic hematopoietic waves characterized by short time windows of emergence and strong overlapping tendencies. Primitive hematopoietic progenitors are rapidly consumed and the engagement of EMPs and LMPs in FL hematopoiesis reduces the expression of c-kit on their surface. Thus, later tamoxifen injection (such as at E11.5) could restrict the labeling to newly derived HSCs expressing high level of c-kit without labeling precedent progenitor waves (87). Such model might be interesting to study the progeny of late HSCs although the risk of tagging the progeny of EMPs and LMPs or later committed progenitors derived from HSCs remains high and difficult to exclude. Further analysis would be necessary to clarify the potential of such model.
Mentions: The contribution of HSCs to FL hematopoiesis is complex to evaluate, partly because of the lack of specific fate-mapping models, and also the relatively limited knowledge regarding embryonic HSC maintenance and homeostasis in this environment. The capacity for long-term reconstitution, which defines functional HSCs, is present in the AGM by E10.5 (76). However, lineage-specific commitment may not occur in vivo immediately after reaching the FL environment. A number of other progenitors generated during transient definitive hematopoiesis, as discussed above, are already present and able to give rise to almost all cell lineages, which could prevent HSC consumption and differentiation (Figure 5). Evaluation of HSC contribution has long been based on the assumption that all hematopoietic cells in the FL were derived from HSCs as is the case in the BM (81). Many multipotential progenitors share the same phenotype with pre-HSC and HSCs, such as the expression of CD41 and AA4.1 (60), adding to this confusion. The combination of the marker Sca-1 and new markers such as those from the SLAM family (82) have greatly helped to clarify the characterization of HSCs, defined now as Lin−ckit+Sca-1+CD150+CD48−CD244−. However, no specific fate-mapping model exists to characterize embryonic HSC progeny with the exception of the Flt3-Cre model (83), which was used until now with the assumption that embryonic and adult HSCs follow similar differentiation pathways. Our recent report suggests that the Flt3-Cre model can also be used to follow the progeny of LMPs (15). Furthermore, in the nascent BM, the long-term repopulation (LTR) capacity that characterizes functional HSCs is only observed at around E17.5 (84). Considering the time required to initiate full HSC differentiation, these data suggest that proper adult HSC-derived hematopoiesis does not take place in the BM until a few days after birth. Characterization of the functional specificities and regulatory pathways of HE that give rise to HSCs versus those that generate EMPs and other multipotential progenitors could aid the development of new fate-mapping models and improve our understanding of this process (85). Use of other fate-mapping models such as the Runx1-Mer-Cre-Mer (Runx1-iCre) (86), Tie2-Mer-Cre-Mer mice (14), and the c-kit-Mer-Cre-Mer mice (87) provided complementary results, although a careful analysis of the targeted cells in time and space is not yet fully available for the last two models. We present here our best interpretation of the data provided in these two recent studies that have used these models in light of the literature and our own results and experience using the Runx1-iCre model (Figure 6).

Bottom Line: The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently.These tissue-resident macrophages derive from sequential seeding of tissues by two precursors during embryonic development.Thus, hematopoietic stem cell-independent embryonic precursors transiently present in the YS and the FL give rise to long-lasting self-renewing macrophage populations.

View Article: PubMed Central - PubMed

Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR) , Singapore , Singapore.

ABSTRACT
The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. Originally described as part of the mononuclear phagocyte system, macrophages were long thought to derive solely from adult blood circulating monocytes. However, accumulating evidence now shows that certain macrophage populations are in fact independent from monocyte and even from adult bone marrow hematopoiesis. These tissue-resident macrophages derive from sequential seeding of tissues by two precursors during embryonic development. Primitive macrophages generated in the yolk sac (YS) from early erythro-myeloid progenitors (EMPs), independently of the transcription factor c-Myb and bypassing monocytic intermediates, first give rise to microglia. Later, fetal monocytes, generated from c-Myb(+) EMPs that initially seed the fetal liver (FL), then give rise to the majority of other adult macrophages. Thus, hematopoietic stem cell-independent embryonic precursors transiently present in the YS and the FL give rise to long-lasting self-renewing macrophage populations.

No MeSH data available.


Related in: MedlinePlus