Lineage determination in haematopoiesis: Quo Vadis?
2
Letters Lineage determination in haematopoiesis: Quo Vadis? Geoffrey Brown 1 and Rhodri Ceredig 2 1 School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK 2 Regenerative Medicine Institute, NCBES, Department of Physiology, National University of Ireland, Galway, Ireland ‘Classical’ models of haematopoiesis depict a branching tree in which the first bifurcation gives rise to separate progenitors for the myeloid/erythroid and lymphoid families of cells [1]. This simple view has been challenged by the identification of haematopoietic progenitors that generate both lymphocytes and myeloid cells but not eryth- rocytes or megakaryocytes (reviewed in [2,3]). To progress further in our understanding of haematopoietic, two issues need to be resolved (i) to arrive at a consensus on the precise relationships between the various haematopoietic lineages, and (ii) to learn how cells gain access to their final mono-lineage fate at the expense of other options. Based on embryology, Holtzer argued that all cell fate decisions are binary [4] – cell lineage trees can only consist of a sequence of bifurcations. Another way of viewing lineage decisions is that the process is stochastic, as proposed some time ago by Ogawa [5]. Later considerations, suggesting that random fluctuations in the levels of transcription factors might govern choices, highlighted the possibility that one pre- cursor cell might sometimes be in a state that allows it to move directly towards any of three or more fates [6]. Controversies over mapping haematopoiesis have led to models that veer away from ‘classical’ bifurcating tree maps. Kawamoto and Katsura term their recent model as ‘myeloid-based’ [3] (see Figure 1, panel A). They suggest that blood cells can be categorised as either ‘prototypic’ or ‘accessorised’. From a consideration of the evolutionary histories of the various haematopoietic lineages that are involved in defending organisms against infections, cells of the phagocytic and myeloid lineages exhibit prototypic functions. By contrast, those haematopoietic cells that exercise the more advanced functions found in ‘higher’ metazoans (for example, erythrocytes and the various lymphocyte classes) can be considered as ‘accessorized’ cells. In ‘accessorized’ cells, many of the ‘prototypic’ activities are modified or shut off, and acquisition of new cellular activities has generated cells with specialised functions. With or with- out these specialisations, however, precursor cells such as thymic T lymphocyte progenitors retain the potential to give rise to macrophages until quite late in their development. The ‘myeloid-based’ model raises interesting questions of where does ‘prototype’ end and ‘accessorizing’ begin – how can cell lineages be delineated? The global family of ‘accessorized’ T lymphocytes include the yet more special- ized CD4 and CD8 cells, together with others (e.g. T helper 1, T helper 2, T helper 17, T reg and T follicular helper subsets of CD4 cells). Dendritic cells (DC) are a problem to place in lineage maps, and it is not clear to what extent the various DCs (plasmacytoid DCs, CD8 + DCs, CD8 DCs, and monocyte-derived DCs) should be regarded as one cell type. Perhaps all the above leads towards the notion that tran- sitions between lineage fates are a continuum and that commitment is a graded phenomenon. Another movement away from the ‘classical’ model is the notion of multiple routes toward a particular end fate. Ye and Graf envisage separate maps for haemato- poietic stem cell development in the bone marrow and the thymus, and major and minor pathways towards erythrocytes/megakaryocytes and myeloid cells [7]. Lai and Kondo propose two branch points towards myeloid cells, and multiple branch points towards T lymphocytes [8]. Our viewpoint on haematopoiesis is that there are pair-wise relationships between fates, and we have placed these as a continuum around a broken circle ([2] and see Figure 1, panel B). This model takes into account multiple pathways as it does not dictate under- lying branch points. Each fate, other than those at the ends of the circle, has two pair wise relationships, so there are two possible ‘preferred’ routes. In ordering fates around a circle, there appears to be consensus as to close relationships between the potentials from mega- karyocytes through to monocytes (see figure b). From there on, the precise relationships are less clear, and Kawamoto and Katsura have noted that this circular model cannot account for T cell progenitors lacking B cell, but retaining myeloid potential. One possible expla- nation for this is that the strong Notch signalling to which thymic-settling progenitors are subjected to in the thymus might subvert the order of commitment of cells in the bone marrow where Notch signalling is relatively weak. At present, it is not clear which, or whether any, of the many recent attempts to re-depict haematopoiesis will emerge as the next widely favoured view of this process. That progenitor cells develop towards a mono-lineage fate by multiple routes and retain other potentials until quite late, points to a dynamic and reversible decision- making process within cells. That reversibility is possible has been clearly demonstrated [9]. We are then left with describing the circuitry of transcription factor activities (see [2]), particularly connectivity, which underpins certain developmental relationships between blood cell types. Despite haematopoiesis being a para- digm for studying cell lineage determination, we still have a long way to go in order to fully understand this process. Update Corresponding author: Brown, G. ([email protected]) 465
-
Upload
geoffrey-brown -
Category
Documents
-
view
214 -
download
0
Transcript of Lineage determination in haematopoiesis: Quo Vadis?
Letters
Lineage determination in haematopoiesis: Quo Vadis?
Geoffrey Brown1 and Rhodri Ceredig2
1 School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston,
Birmingham B15 2TT, UK2 Regenerative Medicine Institute, NCBES, Department of Physiology, National University of Ireland, Galway, Ireland
Update
‘Classical’ models of haematopoiesis depict a branchingtree in which the first bifurcation gives rise to separateprogenitors for the myeloid/erythroid and lymphoidfamilies of cells [1]. This simple view has been challengedby the identification of haematopoietic progenitors thatgenerate both lymphocytes andmyeloid cells but not eryth-rocytes or megakaryocytes (reviewed in [2,3]). To progressfurther in our understanding of haematopoietic, two issuesneed to be resolved (i) to arrive at a consensus on theprecise relationships between the various haematopoieticlineages, and (ii) to learn how cells gain access to their finalmono-lineage fate at the expense of other options. Based onembryology, Holtzer argued that all cell fate decisions arebinary [4] – cell lineage trees can only consist of a sequenceof bifurcations. Another way of viewing lineage decisions isthat the process is stochastic, as proposed some time ago byOgawa [5]. Later considerations, suggesting that randomfluctuations in the levels of transcription factors mightgovern choices, highlighted the possibility that one pre-cursor cell might sometimes be in a state that allows it tomove directly towards any of three or more fates [6].
Controversies over mapping haematopoiesis have ledto models that veer away from ‘classical’ bifurcating treemaps. Kawamoto and Katsura term their recent modelas ‘myeloid-based’ [3] (see Figure 1, panel A). Theysuggest that blood cells can be categorised as either‘prototypic’ or ‘accessorised’. From a consideration ofthe evolutionary histories of the various haematopoieticlineages that are involved in defending organismsagainst infections, cells of the phagocytic and myeloidlineages exhibit prototypic functions. By contrast, thosehaematopoietic cells that exercise the more advancedfunctions found in ‘higher’ metazoans (for example,erythrocytes and the various lymphocyte classes) canbe considered as ‘accessorized’ cells. In ‘accessorized’cells, many of the ‘prototypic’ activities are modified orshut off, and acquisition of new cellular activities hasgenerated cells with specialised functions. With or with-out these specialisations, however, precursor cells suchas thymic T lymphocyte progenitors retain the potentialto give rise to macrophages until quite late in theirdevelopment.
The ‘myeloid-based’ model raises interesting questionsof where does ‘prototype’ end and ‘accessorizing’ begin –
how can cell lineages be delineated? The global family of‘accessorized’ T lymphocytes include the yet more special-ized CD4 and CD8 cells, together with others (e.g. T helper1, T helper 2, T helper 17, T reg and T follicular helper
Corresponding author: Brown, G. ([email protected])
subsets of CD4 cells). Dendritic cells (DC) are a problem toplace in lineage maps, and it is not clear to what extent thevarious DCs (plasmacytoid DCs, CD8+DCs, CD8�DCs, andmonocyte-derivedDCs) should be regarded as one cell type.Perhaps all the above leads towards the notion that tran-sitions between lineage fates are a continuum and thatcommitment is a graded phenomenon.
Another movement away from the ‘classical’ model isthe notion of multiple routes toward a particular endfate. Ye and Graf envisage separate maps for haemato-poietic stem cell development in the bone marrow andthe thymus, and major and minor pathways towardserythrocytes/megakaryocytes and myeloid cells [7]. Laiand Kondo propose two branch points towards myeloidcells, and multiple branch points towards T lymphocytes[8]. Our viewpoint on haematopoiesis is that there arepair-wise relationships between fates, and we haveplaced these as a continuum around a broken circle([2] and see Figure 1, panel B). This model takes intoaccount multiple pathways as it does not dictate under-lying branch points. Each fate, other than those at theends of the circle, has two pair wise relationships, sothere are two possible ‘preferred’ routes. In orderingfates around a circle, there appears to be consensus asto close relationships between the potentials from mega-karyocytes through to monocytes (see figure b). Fromthere on, the precise relationships are less clear, andKawamoto and Katsura have noted that this circularmodel cannot account for T cell progenitors lacking Bcell, but retaining myeloid potential. One possible expla-nation for this is that the strong Notch signalling towhich thymic-settling progenitors are subjected to in thethymus might subvert the order of commitment of cellsin the bone marrow where Notch signalling is relativelyweak.
At present, it is not clear which, or whether any, of themany recent attempts to re-depict haematopoiesis willemerge as the next widely favoured view of this process.That progenitor cells develop towards a mono-lineagefate by multiple routes and retain other potentials untilquite late, points to a dynamic and reversible decision-making process within cells. That reversibility ispossible has been clearly demonstrated [9]. We are thenleft with describing the circuitry of transcription factoractivities (see [2]), particularly connectivity, whichunderpins certain developmental relationships betweenblood cell types. Despite haematopoiesis being a para-digm for studying cell lineage determination, we stillhave a long way to go in order to fully understand thisprocess.
465
Figure 1. Some new ways of viewing commitment to fates during haematopoiesis.
(a) In the classical model [1] the haematopoietic stem cell makes an early choice between lymphoid and myeloid cell fates resulting in these two distinct families of cells. A
recent ‘myeloid-based model’ postulates that myeloid cells represent a prototype of blood cells that are equipped with the basic host defense machinery. Erythroid, T and B
lymphocytes are more specialized cells which have shut-off basic machinery to varying extents as they acquire more functions [3]. (b) The model we have proposed for
haematopoiesis envisages simple pair wise relationships between cell fates [2]. Known intermediate progenitors that encompass contiguous sets of fates are shown on the
diagram. A substantial number of intermediary progenitor cells are possible with each encompassing a different group of fates that are contiguous in the continuum.
Centrifugal closure of fates is envisaged whereby the last fates to be closed are those adjacent to the chosen option. How best to order potentials that appear late in the
sequence along the broken circle is debateable. Modification of our original model (B left, and which we still favour) provides a viewpoint (B, right) that fits with thymic T
lymphocyte progenitors having myeloid potential though not B cell potential if there is centrifugal closure of fates. However, that B lymphocytes and monocytes are close
relatives is equally justified and favours our preferred sequence. Part a modified, with permission, from [3] � (2009) Elsevier. Part b modified, with permission, is from [2] �(2009) Macmillan Magazines Ltd.
Update Trends in Immunology Vol.30 No.10
AcknowledgementWe thank Bob Michell for intellectual input to our model.
References1 Weissman, I.L., Anderson, D.J. and Gage, F. (2001) Stem and progenitor
cells: origins, phenotypes, lineage commitments, andtransdifferentiations. Annu Rev Cell Dev Biol 17, 387–403
2 Ceredig, R., Rolink, A.G. and Brown, G. (2009) Models ofhaematopoiesis: seeing the wood for the trees. Nat Rev Immunol 9(4), 293–300
3 Kawamoto, H. andKatsura, Y. (2009) A new paradigm for hematopoieticcell lineages: revision of the classical concept of the myeloid-lymphoiddichotomy. Trends Immunol 30 (5), 193–200
4 Holtzer, H. (1979) Stem cell concepts: comments and replies.Differentiation 14, 33–40
466
5 Ogawa, M., Porter, P.N. and Nakahata, T. (1983) Renewal andcommitment to differentiation of hemopoietic stem cells (aninterpretive review). Blood 61 (5), 823–829
6 Enver, T. and Greaves, M. (1998) Loops, lineage, and leukemia. Cell 94(1), 9–12
7 Ye, M. and Graf, T. (2007) Early decisions in lymphoid development.Curr Opin Immunol 19 (2), 123–128
8 Lai, A.Y. and Kondo, M. (2006) Asymmetrical lymphoid and myeloidlineage commitment in multipotent hematopoietic progenitors. J ExpMed 203 (8), 1867–1873
9 Cobaleda, C., Jochum, W. and Busslinger, M. (2007) Conversion ofmature B cells into T cells by dedifferentiation to uncommittedprogenitors. Nature 449 (7161), 473–477
1471-4906/$ – see front matter � 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.it.2009.07.003 Available online 21 August 2009
