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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

Timeline of fetal and adult hematopoiesis. The primitive hematopoiesis is initiated in the yolk sac independently of C-Myb activity, and generates early CSF-1R+ EMPs that give rise to YS macrophages without monocytic intermediates during a short time window and will establish the brain microglia. The transient definitive hematopoiesis and then the definitive hematopoiesis are both dependent on C-Myb activity and generate progenitors that differentiate in the fetal liver. The transient definitive wave, which include EMPs and then LMPs, give rise in particular to fetal monocytes that seed the tissues prior to birth to establish the self-renewing tissue-resident macrophage network. Although only HSCs, which result from the definitive hematopoiesis, seem to be maintained in the bone marrow in adults, the relative contribution of the transient definitive wave to the adult immune system remains unclear.
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Figure 5: Timeline of fetal and adult hematopoiesis. The primitive hematopoiesis is initiated in the yolk sac independently of C-Myb activity, and generates early CSF-1R+ EMPs that give rise to YS macrophages without monocytic intermediates during a short time window and will establish the brain microglia. The transient definitive hematopoiesis and then the definitive hematopoiesis are both dependent on C-Myb activity and generate progenitors that differentiate in the fetal liver. The transient definitive wave, which include EMPs and then LMPs, give rise in particular to fetal monocytes that seed the tissues prior to birth to establish the self-renewing tissue-resident macrophage network. Although only HSCs, which result from the definitive hematopoiesis, seem to be maintained in the bone marrow in adults, the relative contribution of the transient definitive wave to the adult immune system remains unclear.

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)

Timeline of fetal and adult hematopoiesis. The primitive hematopoiesis is initiated in the yolk sac independently of C-Myb activity, and generates early CSF-1R+ EMPs that give rise to YS macrophages without monocytic intermediates during a short time window and will establish the brain microglia. The transient definitive hematopoiesis and then the definitive hematopoiesis are both dependent on C-Myb activity and generate progenitors that differentiate in the fetal liver. The transient definitive wave, which include EMPs and then LMPs, give rise in particular to fetal monocytes that seed the tissues prior to birth to establish the self-renewing tissue-resident macrophage network. Although only HSCs, which result from the definitive hematopoiesis, seem to be maintained in the bone marrow in adults, the relative contribution of the transient definitive wave to the adult immune system remains unclear.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585135&req=5

Figure 5: Timeline of fetal and adult hematopoiesis. The primitive hematopoiesis is initiated in the yolk sac independently of C-Myb activity, and generates early CSF-1R+ EMPs that give rise to YS macrophages without monocytic intermediates during a short time window and will establish the brain microglia. The transient definitive hematopoiesis and then the definitive hematopoiesis are both dependent on C-Myb activity and generate progenitors that differentiate in the fetal liver. The transient definitive wave, which include EMPs and then LMPs, give rise in particular to fetal monocytes that seed the tissues prior to birth to establish the self-renewing tissue-resident macrophage network. Although only HSCs, which result from the definitive hematopoiesis, seem to be maintained in the bone marrow in adults, the relative contribution of the transient definitive wave to the adult immune system remains unclear.
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