The development of cell lineages: A sequential model

Differentiation (1988) 39:83-89 Differentiation Ontogeny and Neoplasia 0 Springer-Verlag 1988

Models and hypotheses

The development of cell lineages : A sequential model Geoffrey Brown *, Christopher M. Bunce Janet M. Lord ’, and Fiona M. McConnell

Department of Immunology, University of Birmingham, Edgbaston, Birmingham, B15 2TJ, UK Department of Biochemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TJ, UK

Abstract. The concept of cell lineage and the empirical characterization of specific lineages provide valuable insight into the problems of developmental biology. Of central interest is the decision-making process that results in the diversification of cell lines. Studies of the haemopoietic system, in which stem cells can be committed to one of at least six pathways of differentiation, have suggested that the restriction of differentiation potentials is a progressive and stochastic process. We have recently proposed an alternative model which hypothesizes that lineage potentials during haemopoiesis are expressed individually and in a predetermined sequence as progenitor cells mature. The model first arises from experimental studies which show that both normal myeloid progenitor cells and a human promyeloid cell line, which are able to differentiate towards either neutrophils or monocytes, express these potentials sequentially in culture. The close linear relationship between other haemopoietic progenitor cells is inferred from collective data from studies of bipotent progenitor cells and of haemopoietic proliferative disorders. If the development of haemopoietic cell lineages shows a tendency to follow a particular program, such a mechanism is likely to operate throughout development. In this paper we consider the evidence in favour of programmed events within progenitor cells implementing diversification, and the implications of predetermined and restricted pathways of embryonic development.

Introduction

The processes by which the fertilized ovum and successive generations of cells give rise to a variety of functionally mature cells constitute a central problem in developmental biology. In considering the mechanism involved, the concept of cell lineage is fundamentally relevant. As it is gener- ally understood, the term cell lineage refers to the progression of precursors of a particular cell type. The appropriate description of cell lineages depends on two important points of information. The first is the thread of common identity which can be traced through the precursors of a fully differ- entiated cell. Such commonality is recognized when assigning cells, for example, to a mesoderm, ectoderm or endoderm embryonic origin, where markers are available or can be introduced [18, 20, 49, 631. However, the formation of specialized tissues is a progressive phenomenon ; many gen-

* To whom offprint requests should be sent

erations of cells lie between those making up the blastocyst and the mature constituents of organs. Understanding the precise relationship between the various generations re- quires consideration of the second crucial point: the nature of the decision-making process(es) that produce(s) distinct cell lineages.

It has been suggested that the appropriate conduct of development is sufficiently complex to warrant the dedica- tion of a sizeable set of genes from amongst the total cell DNA [2]. Bailey’s theoretical expansion [2] of this idea proposes a mechanistically precise program for the progress of development, a program which can nonetheless be chron- ologically flexible and can respond to circumstance. His model is adapted and extended from earlier hypotheses put forward by Jacob and Monod [26] and by Britten and Da- vidson [4, 131. The figurative framework of the model is the ‘gene activities tree’ in which the progressive development of cells towards a mature endpoint is achieved by the progressive activation of subsets of the genome control- ling development. The differences between successive co- horts of cells can be ascribed to changes in the activities of these genes between mother and daughter cells. Accord- ing to the model, such changes produce branch-points in cell lineage, and are induced by the action of intrinsic or extrinsic factors on specific units in the set of genes directing development.

A crucial implication of Bailey’s hypothesis is that groups of genes are expressed sequentially, transiently, and in localized groups of homogeneous cells throughout onto- genesis [2]. In this paper we summarize our sequential model for cell differentiation [5, 71, derived from detailed studies on myeloid cell lines, and carrying essentially the same implication as the Bailey model. The concept of pathways of progenitor cell development proposed for the haemopoietic system is extended to the developing organism as a whole.

A system for modelling differentiation

An understanding of cell growth and differentiation in the myelopoietic system has been derived from the study of a culture system which selects for myeloid progenitor cells [36] and from the identification and characterization of various myeloid regulatory factors [37], thus providing a sound base for investigating cell-lineage development. Within this system, the rationale for describing blood granulocytes and monocytes as distinct cell types is straightforward, since

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A

B

Fig. IA, B. Alternative models of commitment to neutrophil and monocyte differentiation. A A progenitor cell (GM) gives rise stochastically to cells (G and M ) committed to the two pathways of differentiation. B The two potentials for differentiation are expressed sequentially

they are morphologically and functionally diverse to a con- siderable degree. The terms ‘granulocyte lineage’ and ‘ monocyte lineage’ can therefore be used to encompass the continuous spectra of cells progressing identifiably towards their respective mature end cells. However, an important conceptual difficulty is raised by the question: do cells which are restricted to either granulocyte or monocyte differentiation belong to the same or different cell lineages? The difficulty is not merely semantic, since assigning progenitor cells to cell lineages is prerequisite for understanding the sequence of development. The two possible answers: that the granulocyte and monocyte progenitor cells belong to different or to the same cell lineages, are illustrated in Fig. 1. In the case where the progenitor cells belong to distinct cell lineages, an ancestral cell gives rise, stochastically, to cells committed either to the granulocyte or to the monocyte pathways of differentiation [42, 55, 581. Thus, the two progenitor cells are diverse in having progressed along distinct pathways of terminal maturation (see Fig. 1A). The alternative hypothesis is that the two progenitor cells are related in a linear manner, rather than having diversified along two distinct pathways, and is the basis of the sequential model of differentiation.

The sequential model

The model proposes that differentiation potentials are expressed in an ordered, linear sequence. During myelopoiesis, progenitor cells first acquire the potential for granulocyte differentiation; later, as this capacity is lost, they express the potential for monocyte differentiation [5 , 71. Sup- port for such a sequence of acquisition of differentiation potentials is provided by studies of nonleukaemic hemopoietic precursor cell lines [15] and of the bipotent promyeloid leukaemic cell line HL60 [5]. Variant HL60 lines, with different capacities for neutrophil and monocyte differentiation, have been developed. The variant lines can be ar- ranged in a sequence in which the HL60 cells first acquire

responsiveness to inducers of neutrophil differentiation. This is lost as the sequence proceeds, and later lines become responsive to inducers of monocyte differentiation. The sequence of acquisition of potentials is illustrated in Fig. 1 B, where granulocyte and monocyte progenitor cells are shown to have derived their diversity from progression along a common pathway of development. As part of the model, the term cell lineage can be extended to describe a linear progressive relationship between progenitor cells. The dis- tinction between the alternative schemes shown in Fig. 1 is the timing of the emergence of intrinsic factors determining neutrophil or monocyte differentiation. In Fig. 1 A factors for both are present concomitantly, and in Fig. 1 B they arise in sequence.

We have also proposed the extension of the sequential model to the haemopoietic system as a whole by using data from a variety of investigations. Studies of bipotent progenitor cells and cell lines [5, 71 and the spectrum of cell involvement seen in the myelodysplastic and myeloproliferative disorders [6, 481, indicate particular close relationships between haemopoietic progenitor cells. These can be interpreted to suggest that the potentials for megakaryocyte, erythrocyte, neutrophil, monocyte, B-cell and T-cell differentiation are expressed in that sequence [5, 71. This linear expression of lineage potentials can be illustrated as a defined progression of partially overlapping differentiation options with only one or two choices available at any given stage (see Fig. 2) .

Extending the model

Haemopoietic stem cells are committed to differentiate along at least six maturation pathways throughout life; the processes involved might be expected to parallel the mechanisms of embryonic development. Figure 3 illustrates this concept and the idea that sequential development of progenitor cells occurs from the fertilised egg onwards. The model is compatible with the results of embryological studies, which indicate that cells make binary decisions. For example, the cell-lineage maps for the embryo and for post- embryonic cells of Caenorhabditis elegans reveal that cells follow either of two development programs. The studies of C . elegans also suggest that the differentiation of cells is intrinsically programmed [14, 561. In the mouse, cleaving blastomeres give rise either to inner cell mass or to trophec- toderm cells, and the latter cell population generates either trophoblast giant cells or ectoplacenta and extraembryonic ectoderm [27]. Thus, any one cell or population of cells gives rise to only two different lines of cells. Figure 3 dem- onstrates the nature of such binary decisions: a cell may either continue along its current pathway of progenitor cell development or give rise to a new cell lineage. The new lineage may be either a progenitor or an end-cell lineage.

It can further be speculated that the predictable bifurcation of cell lineages might be effected by the process of cell division, occurring in conjunction with uneven distribution of membrane receptors mediating differentiation. If lineage potentials are expressed individually and sequentially, uneven distribution of the current receptor determining differentiation would suffice to produce a daughter cell differing from both its parent and its sister. The daughter cell with the majority of the determining receptor would most often mature terminally, whilst the other daughter would go on to express the next lineage potential. There

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Msgakaryocytes Erythrocytes Granulocytes Monocytes Bcells T cells

Stem cell

Fig. 2. A proposed ordered process of cell commitment during haemopoiesis. The schematic representation shows gradual acquisition of one differentiation potential followed by loss of this capacity as the next differentiation option is expressed. The sequence runs from left to right and may or may not involve cell divisions

O,/Germ cell lineage

Ojo 0 Haemopoietic cell \t'

cell line 'age

lineage

Fig. 3. Proposed sequential determination during development. The diagram represents the interrelationships between cell lineages, il- lustrating in particular the sequential nature of development in progenitor cell lineages. The vertical axis represents the degree of differentiation or extent of cell diversity; the further a lineage or cell type from the oocyte, the greater its specialisation relative to that original cell. Progenitor cells committed to megakaryocyte (Me), erythroid (E) , neutrophil (G), monocyte (M), B-cell (B), and T-cell ( r ) differentiation are shown to arise in this linear sequence

is evidence for uneven distribution of receptors in developing cells. In the Xenopus oocyte, different receptors appear to be segregated in distinct hemispheres of the cell membrane [44]; if receptor sorting were the process giving rise to different oocyte daughters, it could also be the process implementing each bifurcation in subsequent cell lineages.

Evidence for the model

Studies of haemopoiesis

The question raised by cell diversification is, in essence: What are the rules which govern the expression of the genes for cellular constituents specific to a particular cell type? With respect to the haemopoietic system, our knowledge of specific gene expression is most complete in the case of B and T lymphocytes. The rearrangement of heavy- and light-chain immunoglobulin genes is prerequisite for B-cell differentiation, and proceeds in a programmed manner. Precursor B cells rearrange the immunoglobulin heavy chain genes first, to form a p-chain gene. Next, kappa light chain genes are rearranged; failure to construct a functional kappa gene leads to the rearrangement of the lambda light chain genes [28]. In B cells producing kappa light chains, the lambda genes remain in the germ-line form [24]. A similar programmed rearrangement and expression of receptor genes occurs during T-cell development, in which completed rearrangement occurs first in the y and 6 genes, and the yd heterodimer is the first T-cell receptor to appear. At a later stage of intrathymic development, a- and a-chain genes are rearranged. If the rearrangement of y or 6 is non- productive, the cell continues to rearrange and a genes [451.

At present, it is not known whether other cell types rearrange genes; it is possible that gene rearrangement is pertinent only to receptor diversity. Even if this is so, the data nonetheless demonstrate a predetermined sequence of gene expression in a developmental process. If, on the other hand, the occurrence of gene rearrangement is more wide- spread, it is likely to be integral in the mechanism of cell diversification.

The above evidence for sequential rather than random processes determining gene expression in haemopoietic cells comes from studies of cells within a particular cell lineage. It is unlikely, however, that the mechanisms governing gene availability within a lineage will differ substantially from those modulating the gene expression giving rise to distinct cell lineages from a progenitor cell. For example, the process that generates B and T lymphocyte diversity and that deciding the choice of progenitor cells able to diversify towards either neutrophils or monocytes are unlikely to be different.

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Studies of variant cell lines, derived from the promyeloid cell line HL60, which typify the sequential expression of potentials for neutrophil and monocyte differentiation, provide an argument in favour of linear progressive events during commitment to the expression of the respective mature phenotypes. Changes in the protein phosphorylation patterns for whole cell extracts have been analysed, by two- dimensional (2D) gel electrophoresis, in a panel of variant lines. The phosphorylation status of six proteins differed between the lines ; the differences were progressive and related to the position of the lines in the proposed linear developmental sequence [9]. These data provide a possible link between protein phosphorylation and lineage determination. Of particular interest is a 15-k Da protein which is constitutively phosphorylated in lines restricted to neutro- phi1 differentiation, which typify cells early in the progression. As cells lose this potential and acquire the capacity for monocyte differentiation, the 15-k Da protein is de- phosphorylated, then rephosphorylated during the induc- tion of monocyte differentiation. This sequential change in the phosphorylation status of the 15-k Da protein implies a similar sequential involvement of particular protein kinases and phosphatases [33]. The expression and/or activation of various protein kinases, in appropriate sequence, may be a basic mechanism in the commitment of myeloid progenitor cells to their ultimate differential development [34]. If this were the case, the sequentially active protein kinases concerned with the differential process would be likely to be specific and closely related. Support for this hypothesis can be drawn from the protein kinase literature; multiple forms of the major protein kinases have been described [lo, 12, 541, and some isoforms show restricted tissue distribution [3, 43, 461 and substrate specificities [25, 511, possibly reflecting their specialised cellular function.

Studies of vertebrates

Data obtained from studies of various other vertebrate cell systems also suggest predetermined and sequential processes of cell diversification.

A bipotent progenitor cell population in foetal rats, 0-2A, gives rise to oligodendrocytes and type-2 astrocytes, which appear respectively at birth and 7-10 days postna- tally [39, 471. The temporal disparity in the appearance of the two types of cell can be interpreted to suggest that the 0-2A progenitor cells have two phases of differentiation potential: expression of the first gives rise to oligodendrocytes and of the second produces type-2 astrocytes.

In neural-crest-derived glial cells from dorsal root gan- glia at various stages of chick embryo development, the restriction of lineage potentials appears to be sequential rather than random [ l l , 31, 621. Weston presents a model in which he suggests that precursor cells make a series of binary decisions, resulting in progressive ordered restriction of the options residing in multipotent cells [62]. Weston’s concept of restriction allows the concomitant expression of multiple potentials where the sequential model proposes the availability of only one or two options, but the two schemes have the idea of a predetermined sequence in common. The identification of determinant receptors and their distribution on glial cells at various developmental stages will be decisive in the resolution of this issue.

Progenitor cells in the mouse intestine give rise to at least four cell lineages : columnar, goblet, entero-endocrine

and Paneth cells. Rather than appearing in equal propor- tions, which might be expected if the process of commitment were entirely random, the progenitors of the four cell types occur in the jejunum in the relative quantities 66, 20, 1 and 8, respectively [30]. It is speculated that the number of mitoses that the columnar, mucous, entero-endocrine, and Paneth progenitors undergo to produce the mature cell types are three, two, one and none, respectively [30]. In the diagram summarizing their interpretations, Le- blonde and Cheng show the development of lineages in that order. If the progenitor cells can indeed be placed in a linear sequence, progression along their pathway of development would coincide with loss of proliferative capacity. The earliest stem cell in the sequence would have the grea- test potential for self-renewal, as is the case for the pluripo- tent stem cell of the haemopoietic system [29].

Studies of lower organisms

Evidence which can be used to argue in favour of sequential expression of lineage potentials also emerges from studies of lower organisms. A particularly well-defined system has been provided by investigation of early development in leeches [52, 531.

The ectodermal layer of the germinal band in the glossi- phoniid leeches contains the o blast cells. Normal division produces 0 cell lines and their appropriate end cells. Com- mitment to 0 cell maturity occurs in three successive stages in the descent of o blast cell progeny; achievement of each stage determines the range of mature cell types produced [52]. Although the observed sequence of segregation of descendant cell fates is consistent with Weston’s idea of restriction, it is perhaps more appropriately fitted to the sequential model of progenitor cell development (cf. the generation of progenitor cell lineages in Fig. 3). The three stages of 0 line commitment have been shown by Shank- land [52] to result from asymmetrical cell divisions, in which one daughter cell remains uncommitted. He suggests that the asymmetry may be generated by differential localisation of determinants within the cell cytoplasm [52, 531, a mechanism analagous to the uneven receptor distribution dis- cussed above.

Species of the slime mould (Dictyostelium) may aggre- gate and differentiate to produce spore and stalk cells. Late in aggregation, all cells develop features characteristic of prespore cells, at which stage there is no indication of cells becoming committed to either spore- or stalk-cell differentiation [50]. The authors propose that the generation of stalk cells involves “redifferentiation ” of cells which had initially prepared to become spore cells. It is not clear that redifferentiation needs to be invoked, since the prespore stage may represent a first phase in the development of the cells, to be succeeded by a phase when the potential to mature to stalk cells is expressed. If this is the case, cells which ultimately become stalk cells will be those which have not passed a point of complete restriction to spore cell formation.

In studies of the sea urchin embryo, two germ-layer- specific molecules have been described, whose expression coincides with the formation of two germ layer cell lineages. Mesol and Endol antigens are identified by monoclonal antibodies, and are present at the time of mesenchyme-cell delamination and on endoderm cells, respectively. The appearance of Mesol and Endol is sequential, and the antigens

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are restricted to subsets of cells [61]. Without direct tran- scriptional data, it is unclear at what stage during development the genes encoding the Mesol and Endol antigenic determinants are switched on. However, the data raise the possibility that the expression of genes which anticipate the formation of germ cell layers is sequential and not simulta- neous.

Implications of the model

The implications of the model are as follows: 1. Lineage options are programmed within cells and

are thus predetermined. This would provide for the predictable and restricted outcome evident in the development of multicellular organisms.

2. Decision-making in differentiation involves binary choice, which could be effected by cell heterogeneity at cell division. Factors which may be unevenly distributed are receptors and/or other determinants such as DNA binding proteins [57] or the enzymes which modify their activity, e.g. protein kinases [40].

3. According to the sequential model, positional [64] or microenvironmental influences [I 5, 601 would endorse a current potential rather than select one of a number of differentiation options. An appropriate balance between intrinsic programmed events and external influences would ultimately determine the outcome in the generation of particular cell types [23]. Such a balance could arise from progenitor cells expressing receptors in a programmed manner until ‘compatibilities’ with an appropriate microenviron- ment arose (see Fig. 4), or the availability of appropriate growth factors [38] induced differentiation along one pathway of maturation.

The influence of the environment is of significance in the feedback control of the numbers of progenitor cells. T lymphocytes, for example, arise last in our proposed sequence of committment during haemopoiesis, and have been shown to enhance and limit the proliferation of various committed haemopoietic progenitor cells [I, 19, 32, 591.

4. The variety of potentials within a progenitor lineage might be expected to represent the degree of its evolution, and the sequence of appearance of potentials would then be the sequence of evolution of the end-cell types. For in- stance, the steps in the sequence of progenitor-cell develop-

ment during haemopoiesis would have been added on in the order in which the cells appear in phylogeny [S]. This is exemplified by the pattern of evolution of immune func- tions, which is mirrored in the proposed sequence of development of haemopoietic progenitor cells. The phagocytic capacity of macrophages and their nonspecific recognition of pathogens is a primordial defense mechanism; lymphocytes and specific immunity appeared later in evolution [17, 351. The coagulation function of platelets may represent a defense mechanism which evolved prior to phagocytosis.

5. Characterization of progenitor cell lineages and their linear sequences should provide important aids to the understanding of the origin and progression of disease in malignancy, which may often involve transformation of progenitor cells [21, 22, 291. Conversely, careful analysis of the various cell types involved in malignant conditions and of disease progression may provide vital insight into the detailed mechanisms of lineage determination.

Concluding remarks

In conclusion, there is some controversy over the mode of lineage restriction during development. Data from various studies suggest that the restriction of development potentials is either a stochastic and progressive process or follows a defined sequence of events. The case for a programmed and sequential organization of the development of the multicellular organism is put comprehensively in a theoretical model by Bailey [2]. Empirical evidence for sequential commitment of stem cells suggests that the process could involve either a predetermined loss of differentiation options [41, 621, or a sequence of availability of lineage potentials [5, 71. In considering the haemopoietic system, the most favoured model at present is one in which the restriction in differentiation potentials of stem cells is progressive and random. However, the data obtained from various studies of haemopoiesis can also be interpreted to suggest that there is a preferred course of lineage commitment. Support for this notion, that differentiation is programmed within cells, can be obtained from studies of a variety of cell systems. Included are studies of differential processes in lymphocytes, neural and intestinal cells and in leech embryos, sea urchins and slime moulds. The idea that choices during cell diversification do arise in a particular order is thus preferred to a stochastic model of haemopoiesis.

Megakaryocytes /- Stem cells for differentiation

0 /” Erythrocytes

Fig. 4. Ordered determination and proposed microenvironmental influences. The lineage option may be endorsed by external influences as the appropriate potential is expressed by interaction of the predetermined progenitor cell with critical proximal cells

W

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The proposal that lineage determination is an ordered rather than a stochastic process is a testable hypothesis, since the issue can be resolved by the identification of the genes whose expression determines the lineage potential(s) of cells and the specific factors that determine in what order and manner these genes are regulated. The haemopoietic system provides a good framework for modelling the relationships between progenitor cells and for the study of bio- chemical and molecular events effecting determination. Within this framework, it should be possible to identify the factors, e.g. DNA-binding proteins, directly influencing the expression of the genes mediating differentiation toward particular end-cells. The identity of the relevant intrinsic factors regulating myelopoiesis should emerge from the comparison of variant HL60 lines exhibiting different differentiation potentials. It will then be possible to follow the time-course of expression and/or activation of the regulating factors, both in normal progenitor cells and in the sequence of variant HL60 lines that are proposed to represent successive acquisition of neutrophil and monocyte potentials. The demonstration of concomitant or sequential emergence of the regulating factors will refute or endorse the sequential model.

Acknowledgements. Work in our laboratory is supported by the Leukaemia Research Fund. F.M. McConnell is supported by the Royal Society.

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Accepted in revised form October 19, 1988

The development of cell lineages: A sequential model

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