Ontogeny of haematopoiesis

The possibility that the adult human liver might be a site for the differentiation of lymphoid cells is controversial. However, a critical role for the foetal liver in haematopoiesis is well accepted. Development of the human haematopoietic system involves a series of coordinated transformations that commence early in embryonic life. Formation and differentiation of the haematopoietic mesenchyme is initiated around the thirteenth day of gestation, with the formation of the yolk sac.¹ Haematopoiesis is established in the yolk sac by day 16 and, with the establishment of blood vessels, transfers via the circulation to the liver.^{2, 3, 4} At 5–6 weeks gestation, haematopoietic stem cells (HSC) and early progenitor cells proliferate intensely in the liver, undergoing little differentiation, leading to a rapid expansion of their numbers. The expansion phase is followed by maturation of this primitive HSC population, with erythropoiesis commencing at 6 weeks. While erythropoiesis dominates in the foetal liver, myelopoiesis, B and T lymphopoiesis and megakaryocyte production can also be detected.¹ B cells are first detected in the foetal liver at 11–14 weeks. T-cell precursors are first detectable at 7 weeks gestation before thymic colonization, which occurs at 8 weeks.⁵ The bone marrow gradually replaces the foetal liver as the primary haematopoietic site and by the time of birth almost all haematopoiesis appears to take place in the bone marrow. It is currently understood that under normal circumstances liver haematopoietic activity ceases shortly after birth⁶ Figure 1).

Figure 1.

Contribution of various organs to haematopoiesis in the foetus. Adapted from Williams 1995.⁶

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Haematopoietic potential of the adult human liver

While the haematopoietic function of the liver in the human foetus is well documented, the role of the adult human liver (AHL) in haematopoiesis is thought to be relatively minor. In the adult, the bone marrow is understood to be the major site of production of all mature circulating blood cells with the exception of T cells, which require the specialized microenvironment of the thymus to complete their development.³ However, the haematopoietic potential of the liver is retained in the adult human and can become activated, as demonstrated by the extramedullary erythropoiesis that occurs in the liver or spleen at times of severe bone-marrow dysfunction. In addition, in adult humans with normal bone-marrow function, extramedullary erythropoiesis in the liver and reconstitution of multilineage haematopoiesis by donor-derived cells has been reported following liver transplantation.^{7, 8} In the case report described by Collins and colleagues (1993)⁸ CD34⁺ cells of donor origin were detected in the recipients" bone marrow, suggesting that stem cells had migrated from the liver. Recently, normal AHL was shown to contain populations of functional HSC with in vitro myeloid and erythroid differentiation capacity⁹ Figure 2), suggesting haematopoietic potential. Using two-colour flow cytometry, we detected hepatic HSC at levels sixfold higher than matched peripheral blood, but comparable to levels detected in bone marrow. Studies in mice have revealed levels of adult hepatic HSC to be approximately 50% those of bone marrow.¹⁰ Therefore, the AHL is a richer source of HSC than murine liver. There was considerable variation in the levels of HSC detected in the individual samples (range 0.82–2.87%) and this may reflect variation in individual status with respect to infection, diet and genetic background.

Figure 2.

Haematopoietic stem cells derived from normal adult human liver tissue give rise to (a) erythroid and (b) monocytic/granulocytic colonies in methylcellulose cultures (Crosbie et al. 1999).⁹

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Characterization of haematopoietic progenitor cell populations in adult human liver

The maturation of pluripotent HSC (PHSC) into non-lineage committed and subsequent lineage-committed progenitor cell populations is accompanied by changes in cell surface antigens. Using monoclonal antibodies (mAb) directed against specific cell surface markers, it is possible to discern the differentiation status and potential of these cells. All mature circulating blood cells are derived from self-renewing PHSC characterized by the expression of CD34.¹¹ The CD34 molecule is currently the only available phenotypic surface marker that selectively identifies all lineages of haematopoietic stem/progenitor cells.¹² During differentiation, CD34 is gradually downregulated and progenitors begin to express activation-, differentiation- and lineage-associated antigens as they proliferate and irreversibly commit to development along a particular haematopoietic lineage.^{13, 14} As CD34 begins to be downregulated, the expression of CD38 is concomitantly upregulated. The expression of CD38 is retained on progenitor cells, which commit to differentiation along both the myeloid and lymphoid lineages and, thus, can be considered to be a non-specific marker for HSC differentiation.^{15, 16, 17} While identifying all stem and progenitor cells, CD34 is not exclusively expressed on cells of the haematopoietic lineage. Vascular endothelial cells in human capillaries from most tissues and some large vessels express CD34.¹⁸ The coexpression of CD45 on CD34⁺ cells distinguishes haematopoietic progenitors.¹⁹ Committed progenitor populations can be identified by the coexpression of lineage-specific markers. CD33 coexpression by CD34⁺ cells identifies commitment to the myeloid lineage; CD19, B-cell committed progenitors; CD7, T/NK cell committed progenitors; CD56, NK (and possibly NKT cell) committed progenitors^{13, 14,20} Figure 3).

Figure 3.

The CD34⁺ haematopoietic stem/progenitor cell compartment.

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Phenotypic characterization of hepatic HSC isolated from normal liver demonstrated that the majority display a 'differentiating' phenotype, expressing low levels of CD34 and greater than 50% of hepatic HSC coexpress CD38.²¹ The expression of human leukocyte antigen-DR (HLA-DR) on almost all hepatic CD34⁺ cells provides further evidence that this population of cells is actively differentiating in situ.⁹ In normal liver, coexpression of lineage-specific markers on hepatic HSC (CD34⁺CD45⁺) revealed that less than 5% of differentiating hepatic HSC express the myeloid associated antigen (CD33) and that the majority express lymphoid-associated markers (CD56, CD7, CD19)²¹ Figure 4). This is in contrast to the phenotypic profiles observed in normal bone marrow aspirates, in which the majority of CD34⁺ cells express CD33, with CD19⁺ B-cell precursors comprising approximately 25% and T-cell progenitors (CD7⁺) only 1% of HSC.^{13, 22} The relatively high level of HSC coexpressing CD7 detected in normal liver is consistent with the hypothesis that the liver is a site of extrathymic NK/T lymphoid cell maturation. The coexpression of CD19 on significant populations of hepatic HSC suggests that the hepatic microenvironment may also support B-cell differentiation. Coexpression of CD56 by CD34⁺ haematopoietic cells has not previously been described in humans and is strongly suggestive that NK cells differentiate from these cells in the normal adult liver. It is possible that CD56⁺ T cells also differentiate locally as there is molecular evidence that murine equivalent cells, V14⁺ T cells, mature in the murine liver.²³

Figure 4.

Phenotpe of hepatic haematopoietic stem/progenitor cell populations. Hepatic haematopoietic stem/progenitor cell (HSC) (CD34⁺CD45⁺) populations express low levels of (a) CD34 and many coexpress (b) CD38 consistent with an actively differentiating phentype. (c) Co-expression of lineage-specific antigens suggests a bias towards lymphopoiesis. Error bars represent +SEM.

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Lymphopoietic potential of the adult human liver

Evidence suggests that the normal AHL may support extrathymic T-cell development, as has been demonstrated in mice.²⁴ In humans, RNA transcripts specific for recombinase activating gene-1 (RAG-1) and RAG-2, the cell-specific components required for lymphoid development, have been detected in hepatic lymphocytes (CD2⁺/CD7⁺) isolated from normal liver tissue. In addition, pre-TCR-, a T-cell specific chaperone expressed at an early stage of T-cell development, has been demonstrated in the same cell populations.²⁵ These findings provide strong evidence that T-cell development is ongoing in the normal AHL, and that at least a subset of cells is developing along the T-cell pathway.

Further evidence for a lymphopoietic role for the normal AHL is provided by the phenotypic and functional characterization of lymphocytes derived from normal liver tissue.^{26, 27, 28, 29} These studies have demonstrated that, while the hepatic lymphoid repertoire contains antigen-specific lymphocytes, innate immune cells dominate. Large numbers of T cells, DN and CD8 T cells, NKT lymphocytes (CD3⁺CD56⁺) and V24⁺ cells are found in the liver. The phenotypic and functional properties of these innate hepatic cell populations resemble those of murine lymphocytes, which are thought to be extrathymic in origin.^{23, 30, 31, 32, 33, 34} The origin of human hepatic lymphocyte populations is unknown. Hepatic lymphocyte populations appear to be tissue resident as they are not removed by extensive perfusion of the organ.²⁸ The location of the liver between the gastrointestinal tract and the cardiopulmonary system results in constant exposure to the constituents of the major blood vessels of the body. As a result, there is continuous infiltration of peripheral blood cells into the liver. Selective homing and retention of peripheral lymphocytes and subsequent expansion and induction of cell surface molecules mediated by the hepatic cytokine milieu, may be responsible for the unique nature of hepatic lymphocyte populations. However, studies in mice have demonstrated that in addition to cells derived from the periphery, adult murine hepatic lymphocytes contain populations that are locally derived.³⁵ Given the presence of HSC and the expression of RAG-1, RAG-2 and pT, the 'extrathymic' nature of hepatic lymphocytes taken together with the demonstration of lymphocyte progenitor cell populations provides strong evidence for an active lymphopoietic role for the normal AHL.

The haematopoietic microenvironment of the adult human liver

The importance of the local microenvironment in determining the developmental fate of haematopoietic precursor cells is demonstrated by the ability of cells from the same clone to commit to different lineages under different environmental conditions. Kondo et al. (1997)³⁶ cultured single cells in methylcellulose in the presence of stem cell factor (SCF), IL-7 and flt-3 ligand to expand cell numbers, and a portion of the day three colonies were injected directly into the thymus. The remaining cells in methylcellulose formed B-lineage colonies, but the cells injected directly into the thymus differentiated into all stages of thymic lymphocytes, including mature T cells. Thus, the commitment of common lymphoid progenitors to NK, T- or B-cell lineage may possibly be determined simply by the microenvironment.

The concept of extrathymic T-lymphocyte development predicts that T-cell progenitors, and all factors required for their maturation, are present at extrathymic sites.³¹ The adult murine liver harbours HSC,^{10, 37} and IL-7 produced by parenchymal hepatocytes plays a pivotal role in the generation of murine hepatic extrathymic T lymphocytes.³⁸ The relatively high level of hepatic HSC coexpressing CD7²¹ and the innate phenotype of mature T lymphocytes (in particular the high proportion of CD8, and NKT cells) detected in the normal AHL³⁹ is consistent with the hypothesis that normal AHL can support T lymphopoiesis Figure 5).

Figure 5.

A significantly higher proportion of hepatic T cells display an innate phenotype when compared to matched peripheral blood. Adapted from Doherty and O'Farrelly 2000.³⁹

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In humans, IL-7 is a critical cytokine for normal T-cell development^{40, 41, 42} and IL-15 plays an essential role in the development of NK cells.^{43, 44} Studies in mice suggest that the developmental needs of NKT cells include a dependence on IL-15.⁴⁵ Significant levels of IL-7⁴⁶ and IL-15 protein (L Golden-Mason and C O"Farrelly, unpubl. data, 2001) have recently been demonstrated in normal AHL, suggesting that normal AHL has the potential to provide a suitable microenvironment to support lymphopoiesis Figure 6).

Figure 6.

Haematopoietic cytokine levels in normal liver tissue. Levels of IL-7 and IL-15 were assessed in homogenized liver tissue by ELISA.

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Studies of cytokine receptor expression have proven invaluable in pinpointing where specific ligand-receptor pairs have biological activities. Cytokines are widely expressed in different tissues, in contrast to their receptors, which have a more restricted expression pattern. On average, 61% of CD34⁺CD45⁺ hepatic HSC coexpress IL-15-R (n = 7, range 40.8–78.82%) and 46.66% (range 25.37–61.46%) coexpress IL-7R (L Golden-Mason and C O"Farrelly, unpubl. data, 2001; Figure 7). Hepatic IL-7 and/or IL-15 may act on these progenitor cells to promote their survival and differentiation. Constitutive expression of IL-7 and IL-15 and the expression of receptors for these cytokines on the majority of hepatic HSC lends further weight to the hypothesis that the normal AHL can act as a primary lymphoid organ, as both of these cytokines have been demonstrated to be indispensable for thymic-independent T-cell development.^{32, 45, 47, 48} However, both IL-7 and IL-15 act on a variety of mature leucocytes^{49, 50, 51, 52, 53, 54, 55, 56} and IL-15 also acts on cells that are not of haematopoietic lineage.^{57, 58} Thus, their expression in the liver may be a reflection of a wider role for these cytokines in local immune responses.^{59, 60}

Figure 7.

Hepatic haematopoietic stem/progenitor cells (CD34+ CD45+) express receptors for IL-7 and IL-15. Flow cytometric dotplot of CD45 (FITC) and CD34 (PerCP) staining of hepatic mononuclear cell preparationshowing (a) CD34⁺CD45⁺ cells (R1) gated for analysis. (b) Negative control. Histogram analysis showing (c) IL-15 receptor B-chain (IL-15R) and (d) IL-7R levels on CD34⁺CD45⁺ hepatic progenitors.

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Physiological role of adult hepatic haematopoiesis and lymphopoiesis

The physiological significance of hepatic haematopoiesis in mice is illustrated by activation of this pathway by various stimuli, including syngenic tumours.^{61, 62, 63, 64} In adult mice, hepatic haematopoiesis plays an important role in the generation of innate T cells involved locally in the surveillance and rejection of tumours.^{23, 63,65, 66, 67} It is as yet unknown if a similar mechanism of tumour immunity exists in humans. If a physiologically significant haematopoietic pathway operates in the AHL, one would expect to see activation and/or alterations of this pathway in a situation in which there is a local need for increased numbers of immune effector cells, such as in tumour challenge.

Mature cells of the haematopoietic system of both myeloid (monocytes and neutrophils) and lymphoid (T cells, NK and NKT cells) lineages are believed to play a role in the host response to tumour challenge. Antitumour effector cells can be broadly divided into two groups: early antimetastatic and those involved in the later stages of the elimination of established solid tissue metastases. Kupffer cells^{68, 69} neutrophils⁷⁰ and NK cells⁷¹ have all been implicated in the surveillance and prevention of hepatic metastases. NK1.1 T cells have been postulated to be the principal antimetastatic lymphocyte population in the murine liver⁶⁶ and play an important role in the IL-12-mediated rejection of tumours.⁶⁵ Natural killer cells facilitate the development of tumour-specific cytotoxic T lymphocytes (CTL),⁷² which are believed to be the most important effectors in the rejection of established tumours.⁷³ Natural killer cells themselves may also participate directly in the elimination of established metastases.⁷⁴ The normal AHL contains significant populations of myeloid⁹ and lymphoid progenitors,²¹ activation of which may contribute to the local pool of antitumour effector cells.

Murine studies have demonstrated an increase in the extrathymic differentiation pathway of T cells in the livers of mice bearing syngenic tumours.⁶³ It has also been suggested that in humans, as in mice, T cells of extrathymic origin may be involved in tumour immunity.⁷⁵ Using multiparameter flow cytometry, we found no differences in the levels and activation status of HSC in tumour-bearing liver compared to HSC from normal AHL. Although no overall upregulation of haematopoiesis was observed, changes occurred in the nature of the hepatic haematopoietic pathway. A significant increase in the proportion of hepatic HSC coexpressing the T/NK cell marker (CD7) and a sixfold increase in HSC with an immature myeloid phenotype (CD33⁺) were observed.²¹ Both granulocytes and lymphocytes are generated in the hepatic parenchyma of adult mice,⁷⁶ and the presence of significant levels of hepatic HSC committed to differentiation along the myeloid lineage in human tumour-bearing liver suggests the possibility of local promotion of granular populations. There is evidence to support the existence of an extrathymic adult human T-cell differentiation pathway in the liver.^{9, 21, 25, 46} The presence of CD34⁺CD56⁺ stem cells and large populations of NK cells and NKT lymphocytes is suggestive of local NK and NKT-cell maturation in normal adult liver. The changes observed in the lymphoid compartment of the hepatic haematopoietic system on tumour challenge may reflect a role for in situ T-lymphopoiesis in the surveillance and elimination of hepatic tumours in humans.

Epilogue

It is now accepted that normal adult liver must maintain a complex immunological environment capable of responding to harmful foreign stimuli and tolerating harmless foreign antigens.³⁹ An important additional immunological role may be rapid local production of NK-like lymphoid antitumour effector cells from haematopoietic stem cells located within the liver.

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