Potential Adhesion Mechanisms for Localisation of Haemopoietic Progenitors to Bone Marrow Stroma

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Potential Adhesion Mechanisms for Localisation of HaemopoieticProgenitors to Bone Marrow StromaPaul J. Simmons a; Andrew Zannettino a; Stan Gronthos a; David Leavesley a

a Matthew Roberts Laboratory, Leukaemia Research Unit, Division of Haematology, Hanson Centre forCancer Research, Adelaide, South Australia

To cite this Article Simmons, Paul J., Zannettino, Andrew, Gronthos, Stan and Leavesley, David(1994) 'Potential AdhesionMechanisms for Localisation of Haemopoietic Progenitors to Bone Marrow Stroma', Leukemia and Lymphoma, 12: 5, 353— 363To link to this Article: DOI: 10.3109/10428199409073776URL: http://dx.doi.org/10.3109/10428199409073776

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Potential Adhesion Mechanisms for Localisation of Haemopoietic Progenitors to

Bone Marrow Stroma PAUL J. SIMMONS, ANDREW ZANNETTINO, STAN GRONTHOS and DAVID LEAVESLEY

Matthew Roberts Laboratory, Leukaemia Research Unit, Division of Haematology, Hanson Centre for Cancer Research, Adelaide, South Australia, 5000

(Received 30 May 1993)

Haemopoiesis occurs in intimate physical association with the stromal elements of the bone marrow. Current evidence supports the hypothesis that the restriction of primitive haemopoietic progenitor cells (HPC) to the bone marrow involves developmentally regulated adhesive interactions between HPC and the stromal cell microenvironment. This review ex- amines the expression and function of cell adhesion molecules (CAM) on human HPC and marrow stromal cells. These data demonstrate that a broad range of CAMS representing at least three adhesion molecule superfamilies (integrins, selectins, immunoglobulin gene superfamily) participate in these adhesive interactions. We discuss the potential contribution of these various adhesion molecules to homing of HPC to the bone marrow, their retention within the extravascular haemopoietic compartment and their egress into the peripheral circulation. It is likely that each process is mediated not by a single binding event but requires the co- ordinated participation of multiple receptor-ligand pairs.

KEY WORDS: bone marrow stroma

STROMAL CELLS AND THE RESTRICTION OF HAEMOPOIESIS TO THE BONE MARROW

The importance of cellular interactions in haemopoietic cell development is well established. '-* De- spite this, precise definition of the nature of many of these interactions at a molecular level is lacking and remains an objective which is of fundamental importance to our understanding of the regulation of haemopoiesis. Under steady state conditions the majority of primitive stem cells appear to reside in the bone marrow where they and their progeny develop in as-

Address for correspondence: Paul J. Simmons, Matthew Rob- erts Laboratory, Leukaemia Research Unit, Division of Haema- tology, Hanson Centre for Cancer Research, Frome Road, P.O. Box 14, Rundle Mall, Adelaide, South Australia 5000.

adhesion haemopoietic progenitors

sociation with a phenotypically and probably func- tionally heterogeneous population of stromal cells .7s9-15

The various cellular elements of the stroma together with their associated biosynthetic products including extracellular matrix (ECM) components and haemopoietic growth factors (HGF) constitute the haemopoietic microenvironment (HM) of the bone marrow. 1,2,4,7 Accumulating evidence supports the proposal that the localisation of haemopoiesis to the bone marrow involves developmentally regulated adhesive interactions between primitive haemopoietic cells and this complex stromal cell-mediated HM. 16-19 In this review we ,will summarise recent data describing the expression and function of adhesion molecules on primitive human haemopoietic progenitor cells (HPC) and discuss the potential role of these molecules in the homing of HPC to the bone marrow, their retention within the HM and their release into the peripheral circulation.

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P. J. SIMMONS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAETAL. 354 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBACELLULAR INTERACTIONS IN HAEMOPOIESIS: A MULTIPLICITY OF MECHANISMS

The cellular interactions that regulate haemopoiesis are many and varied. This is hardly surprising when one considers the hierarchical nature of the haemopoietic system (with discrete stem cell, progenitor cell and maturing cell compartments), the number of cell lineages generated and the diversity of tissue envi- ronments associated with their development and mat- uration (bone marrow, thymus, secondary lymphoid organs). In all likelihood the molecules which mediate these interactions may function in a stage and/ or lineage-specific manner as occurs, for example in the regulation of T-cell development.20,21 Thus, a zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAva- zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAriety of molecular species are probably involved in supporting a range of interactions throughout haemopoiesis. As this review will show, current data support this hypothesis which, in many respects par- allels the diversity of adhesive interactions involved in regulation of the immune system.20

In recent years there has been an exponential in- crease in our understanding of the mechanisms that regulate cell adhesion in multicellular organisms. A broad range of cell surface moieties have been identified that function as cell adhesion molecules (CAMs) for diverse ligands including integral membrane glycoproteins and ECM components zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA.20,22-24 Several distinct superfamilies of CAMs have been identified including the immunoglobulin gene superfamily, integrins, selectins, cadherins and the CD44 family (Table l ) , many of which are expressed by haemopoietic cells. Studies to investigate the function and contribution of particular CAMs to interactions of HPC with the stromal HM are complicated by the diversity of potential ligands for many of these CAMs which are exhibited by marrow stromal tissue (Table 2). This is further compounded by an additional category of interactions which involve HGF-receptor mediated adhesion of HPC to stromal cell-derived HGF pre- sented either as integral membrane protein^^^,^^ or bound to ECM molecules.27 This multiplicity of potential adhesive mechanisms presents a major technical and conceptual challenge to the identification of those CAM-ligand pairs which are essential for localisation of HPC to the BM. Nevertheless, some likely can- didates are beginning to emerge. These are reviewed below.

Table 1 Cell adhesion molecule superfamilies

Immunoglobulin superfamily of adhesion receptors

ICAM-2 LFA-3 (CD58) MHC

ICAM-3 CD3/T Cell Receptor N-CAM

PECAM- 1 (CD3 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA1) CD8 c-kit

ICAM-1 (CD54) LFA-2 (CDZ) Thy- 1

Class I & I1

VCAM- 1 CD4 Ng-CAM

Cation-dependent CAMS N-Cadherin E-Cadherin P-Cadherin

Integrins Numerous: 8 p-chains & 13 a-chains in multiple

combinations

Selectins P-Selectin L-Selectin E-Selectin

Miscellaneous CD44 S y ndecan CD36

Table 2 ECM, Glycoproteins and CAMs expressed on bone marrow stromal cells

ECM components GAGs/Proteoglycans CAMS

Collagen I Chondroitin sulphate ICAM- 1 (CD54) Collagen 111 Heparan sulphate N-CAM (CD56) Collagen IV CD44 VCAM-1 Collagen V H yaluronate LFA-3 (CD58) Collagen VI Thy- 1 Fibronectin Vitronectin Laminin Thrombospondin Haemonectin

Baaed on data from Zuckerman and Wichd (1983). Long and Dixit (1990). Campbell er zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAal. (19901, Gordon zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA(1988), Gallagher (19891, Simmons zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAernl. (1992), Kincade er ul. (1989). Teixido er 01. (1992) [References 28-35],

INTEGRIN-MEDIATED ADHESION OF HPC

Integrins are a large family of CAMs with well documented roles in a variety of cellular functions including cell migration and tissue organisation during embryonic development, cell differentiation, inflammation and m e t a ~ t a s i s . ~ ~ Integrins mediate both cell- cell and cell-ECM interactions and are so-named because of their ability to integrate the intracellular cytoskeleton with the ECM. Structurally, they rep- resent a phylogenetically conserved family of integral membrane glycoproteins that consist of at least 20 distinct heterodimers formed by non-covalent association between 13 a subunits and 8 different p sub-


MECHANISMS FOR LOCALISATION OF PROGENITORS IN MARROW 355

units, each with distinct ligand-binding properties. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA37.38

Compounding the diversity of adhesive interactions mediated by integrins, most, if not all integrins can assume multiple functional states. 37 The integrins are subdivided on the basis of /I-chain composition although it is important to note that some a-chains (particularly zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAa”) can associate with more than one zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAp subunit (Figure 1) . The zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAp1 (CD29) or Very Late Antigen (VLA) integrins comprise the largest subfamily and mediate cell-ECM and cell-cell adhesion. The p2 (CD18) or leukocyte integrins bind to cell surface counter-receptors of the immunoglobulin gene superfamily and therefore mediate cell-cell adhesion. The /I3 (CD61) or cytoadhesion integrins predominantly bind to ECM proteins (Figure 1).

To date, the majority of published studies have ex- amined the expression of only the pl, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA/ I 2 and zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAp3 in-

tegrins in human bone marrow. 33*35341-45 Of these, p3 (CD61) integrin is present on a minor proportion of CD34’ cells (approximately 10%) which are thought to include megakaryocyte precursors zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA.44,46 The expression of p3 by more primitive HPC with the capacity to initiate and sustain haemopoiesis in long-term marrow culture (so-called long-term culture initiating cells, LTCIC)47 has not been determined. Of the p2 (CD18) integrin family, CDl la (aL) is the only a-chain de- tectable on CD34+ cells (approximately 80%) .35943*48

LTCIC however, are restricted to the CDI la/CD18- subp~pulat ion.~~ There is good evidence for expression of at least one member of the /Il (CD29) integrin family, a4P1 (CD49d/CD29), by human LTCIC33 and because of the brief nature of this overview we will focus on the role of PI integrins in mediating adhesion of HPC to marrow stromal elements.

Col, Fn, Lam Vn, Col, zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA(Lam) Fn,Fg Col, Lam vWF

Fn, Col, Vn vWF, Lam, Fg Tsp, osp, Bsp

Fg, iC3b

FactorX zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAaM ICAM-1

ICAM-1 \ ICAM-3 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA““7 ICAM-2

ax Fg, iC3b

’ a7 a* zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBALam

?

Figure 1 Integrin Pairing and Ligand Specificity. Integrin heterodimers are formed by non-covalent association of unique a chains with one, or more, p chains. Composition of subunit pairs determines ligand specificity. The p4, p5, p6, p7 and p8 integrins have not yet been shown to be expressed by haemopoietic cells and have been omitted for simplicity. Ligands: Col, collagens; Lam, laminin; Fn, fibronectin; VCAM- 1, vascular cell adhesion molecule- 1; Fg, fibrinogen; vWF, von Willebrand Factor; Tsp, thrombospondin; Osp, osteopontin; Bsp, bone sialoprotein; ICAM- 1, intercellular adhesion molecule- 1 ; ICAM-2, intercellular adhesion molecule-2; ICAM- 3, intercellular adhesion molecule-3; iC3b, complement factor 3b.


356 P. J . SIMMONS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAET AL..

INTEGRIN zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAa4/3,: DISTINCT ROLES IN CELL-CELL AND CELL-ECM ADHESION zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAIntegrin zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAa4P, is expressed by a wide variety of circulating lymphoid and myeloid ~ e l l s ~ ~ , ’ ~ and functions as a receptor for two distinct ligands. The first, vascular cell adhesion molecule-I (VCAM-l), a member of the immunoglobulin gene superfamily, is an integral membrane glycoprotein which was first identified as an inducible CAM on human endothelial cells by Bevilacqua and c o l l e a g ~ e s . ~ ~ The second ligand for a4P1 is fibronectin (FN),” a major component of the ECM synthesised by bone marrow stromal cells in vivo and in vitro. Three distinct binding sites for zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAa4P1 have been identified on the FN m o l e c ~ l e . ~ ’ . ~ ~ The sites on a4P1 involved in interaction with FN are distinct from those which bind to VCAM-1.53 a4PI therefore mediates both cell-cell and cell-ECM adhesion.

The pioneering work of Kincade and colleagues first demonstrated the importance of a4P, in regulating haemopoiesis in vitro. Addition of an anti-a, subunit monoclonal antibody (MAb) to murine long term bone marrow culture (LTBMC) was found to completely abrogate lymphopoiesis and to retard myelopoiesis .54

It is not clear from these data however, whether inhibition of cellular adhesion is responsible for the observed suppression or whether some antibody-mediated growth modulatory effect in LTBMC may also be involved. Recent data suggest an equally important role for a4Pl integrin in human haemopoietic cell interactions. Between 46-90% of CD34’ bone marrow cells are reported to co-express zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAa, PI 3333sz43-4s which include the majority of lineage restricted clonogenic progenitors, CFU-GM and BFU-E33,4s and B-cell pre- c u r s o r ~ . ~ ~ Our group has shown, in addition, that LTCIC express a4P1 and that anti-CD49d antibody partially inhibits their adhesion to marrow stromal cells in ~ i t r o . ~ ~ VCAM-1 is constitutively expressed by human bone marrow stromal cells in vitro33*55 and in vivo (SG and PJS; unpublished observations) and its expression can be up-regulated by inflammatory me- diators such as IL- 1, IL-4 and TNFa resulting in con- cordant increases in CD34’ cell adhesion. ’’ Antibody to VCAM-1 partially inhibits the adhesion of LTCIC, myeloid and erythroid progenitors and normal and leukaemic B-lymphoid precursors to cytokine-induced marrow stromal cell^.'^.'^ Thus, in addition to roles in physiological processes involving migration and localisation of immune ~ e l l s , ~ ~ ~ ~ ~ the a4y4pI/VCAM- 1 counter receptors also mediate adhesion of primitive HPC to bone marrow stromal cells.

While there is accordance between different groups concerning the role of VCAM-1 in this setting, con- flicting observations have been made regarding the role of FN, the alternative ligand for a4P1. A number of groups have reported insignificant binding of HPC to

while others have demonstrated adhesion of murines8 and human HPC (including LTCIC) to intact zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAFN or proteolytic fragments there~f .~ ’ ”~ Recent work by Hemler and colleaguesm may, at least in part, re- solve these differing observations. The authors identify 3 activation states of a4PI; the fully active receptor binds both ligands, the inactive form, neither. A third, partially active form of aqP1 binds only to VCAM-1. Thus, in order to bind FN, further activation of a4PI is required. In accord with this, Kerst zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAet d4’ demonstrated the acquisition of a4PI and aspI- dependent adhesion of CD34’ cells to FN following protein kinase C activation. Given the high proportion of CD34’ cells which bind to VCAM- 1’’ collectively these data suggest that HPC constitutively express the partially active form of a4PI.

Antibodies to a4PI or VCAM-1 alone or in com- bination do not completely block the adhesion of HPC to marrow ~ t r ~ m a ~ ~ , ~ ~ , ~ ~ suggesting that more than one CAM interaction is involved in this process. Recent studies in our laboratory have identified several additional CAMS on primitive HPC. These are briefly summarised below.

~ ~ 4 5 . 4 8

PECAM-l/CD31: AN AMPLIFIER OF INTEGRIN-MEDIATED ADHESION

Platelet-endothelial cell adhesion molecule- 1 (PECAM- 1) or CD31 is an immunoglobulin gene superfamily member of 130-kD that is expressed at high density on endothelium, platelets, granulocytes, monocytes and by a subset of l y rnph~cy tes .~ ’ -~~ Although the precise function of CD31 is not known in all cell types that express it, a number of studies clearly document its ability to function as a Our own studies [67 and PJS manuscript submitted for publication] demonstrate that in addition to the abovementioned mature leukocyte populations, essentially all CD34+ cells express CD31; BFU-E at low level, CFU-GM at high level and LTCIC at an intermediate level. Anti- CD31 Fab fragments partially inhibit adhesion of CD34’ cells to marrow ~ t r o m a . ~ ~ Although the ligand for CD31 is not yet defined, sulphated proteoglycans are a possible candidate.68 The latter are produced in abundant quantities by marrow stromal cells6* and have


MECHANISMS FOR LOCALISATION OF PROGENITORS IN MARROW zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA357 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAbeen shown to participate in the adhesion of primitive HPC.70 In addition to its role as a CAM, recent work by Shaw and colleagues has demonstrated a role for CD31 in amplifying PI and P2 integrin-mediated adhesion of T cells.71 Whether CD31 has a similar role on HPC has not been investigated.

THE SELECTINS: ADHESION OF HPC

RECOGNITION MEDIATED BY LECTIN-CARBOHYDRATE

The selectins are three structurally related glycoproteins that participate in leukocyte adhesion to vascular endothelium and platelet^.'^,^^-^^ Leukocyte (L), En- dothelial (E) and Platelet (P)-selectins function as Ca" dependent lectins, mediating rapid, shear-resistant adhesion by recognition of specific carbohydrate ligands.24,16-78 A role for such protein-carbohydrate interactions has already been demonstrated in murine haemopoietic tissues by Tavassoli and colleagues. 1737y

However, few studies have investigated the potential involvement of the selectin family in the interaction of human HPC with the HM.

L-selectin is expressed on mature myeloid cells (neutrophils, eosinophils and monocytes) and most lymphocytes, mediating the adhesion of leukocytes to endothelium at sites of inflammation and homing of lymphocytes to peripheral lymph nodes.247s0781 Our own studies67 demonstrate expression of L-selectin by approximately 75% of CD34' cells which include 290% of CFU-GM and 60% of BFU-E, confirming earlier work by Griffin and colleagues." Additionally, LTCIC express L-selectin at low level and adhere to a TNFa- inducible ligand on marrow stromal cells.67 The nature of the carbohydrate and/or protein components of this L-selectin ligand is not yet established. How- ever, based on studies using murine bone marrow stromal cells it appears to be distinct from the 50 kD sialomucin GlyCAM-1 identified as the ligand for L- selectin on murine peripheral lymph node high endothelial venules (HEV)83 (AZ and PJS; unpublished observations).

P-selectin (CD62) is a receptor for neutrophils and monocytes that is rapidly translocated from secretory granule membranes to the plasma membrane of activated platelets and endothelial cells zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA.24,74,77784 Pre- vious studies have documented expression of P-selectin by a proportion of bone marrow endothelial cells.85 We have recently demonstrated binding of bone marrow CD34' cells, including LTCIC, to purified P-se-

lectin [PJS; manuscript submitted for publication]. Of interest, neither sialyl Le" nor sialyl Lea, both well documented ligands for P-selectin, are expressed by CD34' cells.24 Treatment of CD34' cells with neuraminidase inhibits their adhesion to P-selectin imply- ing a prominent role for sialic acid in the structure and function of the ligand. Antibody HECA 452 which identifies the cutaneous lymphocyte-associated antigen (CLA), a ligand for E-selectin on skin-associated memory T-cells, 86 binds to a neuraminidase sensitive epitope on CD34' cells and partially inhibits their adhesion to P-selectin. We are currently investigating the nature of the glycoprotein identified by HECA- 452 on CD34' cells.

HAEMOPOIETIC PROGENITOR CELL- GROWTH FACTOR INTERACTIONS

Haemopoiesis is regulated by a wide variety of haemopoietic growth factors (HGF). In the context of adhesive interactions between HPC and the stromal HM, HGF are of central importance.

Growth factors which act on HPC have been shown to modulate the adhesive interactions of cells by regulating the expression and/or activation state of CAMs33,73,82,83,87 or by influencing ECM biosynthesis and degradation.87x88 In addition, cell adhesion has been demonstrated to induce the production of HGF by a variety of cell Many HGF are bound in bi- ologically active form by ECM and in this form are able to mediate adhesion of HPC." In addition, certain HGF can exist in both membrane bound and soluble forms. 25v263y2 The integral membrane isoforms of macrophage colony-stimulating factor (M- CSF) and stem cell factor (SCF) are expressed by marrow stromal cells and have been demonstrated to promote the adhesion of cells bearing the appropriate HGF receptors, c-fms and c-kit, respectively.25326 A single receptor-ligand pair is thus able to stimulate HPC proliferation and support HPC-stromal cell adhesion. A number of cell types which express c-kit, including mast cells and megakaryocytes, adhere to marrow fibroblasts via interaction with SCF.25,93 c-kit is expressed by 75% of CD34' cells in the bone marrow, including the majority of CFU-GM, BRJ-E and LTCIC [Reference 94; PJS, G Aylett, LK Ashman; manuscript submitted for publication], Although HPC have not previously been reported to utilize this adhesion mechanism, preliminary data from this laboratory suggest they do and furthermore, that cell-cell adhe-


358 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAP. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAJ. SIMMONS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAETAL.

sion mediated by the c-kit-SCF receptor/ligand pair is additive with respect to that supported by other CAMs such as integrin zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA(~4pI [AZ and PJS; unpublished observations]. At this time it is unclear (1) to what extent binding to immobilized HGFs is utilized by HPC as an adhesive interaction, (2) the range of HGF that mediate cell adhesion, and (3) whether ECM- bound HGF are as effective at promoting adhesion as integral membrane isoforms. This adhesion mechanism clearly warrants further exploration.

OTHER CANDIDATE CAMS

Because of the brief nature of this overview we have, of necessity, focussed on a limited number of CAM- ligand interactions with roles in supporting adhesion between HPC and the marrow stroma. However, other CAMs are clearly involved in this complex process. CD44, the major cell surface receptor for hyaluronic acid95 exhibits multiple activation states96 and exists in a multitude of i s o f o ~ m s . ~ ~ Anti-CD44 antibodies identify primitive human HPC43,98 and marrow stromal cells. Addition of anti-CD44 antibodies to murine LTBMC results in a profound inhibition of haemopoiesis, in particular, B-lymphoid de~e lopmen t .~~ Several CAMs belonging to the Ig superfamily are expressed by human HPC including LFA-3 (CD58),43 ICAM- 1 (CD54) ,4391M) and Thy- 1. ICAM- 1 and Thy- 1 are also present on marrow stromal cells [References 35, 102; SG and PJS; unpublished observations], as is N-CAM (CD56)lo3 but, with the exception of ICAM- 1, have not been shown to participate in adhesive interactions with HPC. CD43, a counter-receptor for ICAM-1,'O4 is expressed at high density by CD34+ cells although its potential role in HPC-stromal cell adhesion has not been investigated. CD34, which shares several biochemical features with CD43 has been speculated to function as a CAM for HPC although such a role has not been documented. In fact, based on recent studies with vascular endothelial cells, CD34 is proposed to have a negative modulating role on cell- cell adhesion, perhaps by increasing the stringency requirements of ligand-receptor interactions that facili- tate adhesion. lo5

A MULTIPLICITY OF CAMS: REDUNDANCY OR COMBINATORIAL DIVERSITY?

There is now considerable data demonstrating that primitive human HPC exhibit a multitude of CAMs

each with specificity for distinct counter receptors on marrow stromal cells. Does this imply redundancy within this repertoire, or do particular CAMs perform separate functions associated with, for example, the homing of HPC to the bone marrow, or their lodgement and retention within the extravascular HM? (Figure 2). Given the potential complexity of both phenomena such an array of CAMs on HPC might be anticipated. Studies of the mechanism of entry of mature leukocytes into tissues provide important insights into this question. From such studies has come the realisation that this is a multi-step process controlled by a dynamic interaction between CAMs expressed by both leukocytes and endothelial cells. Three fam- ilies of CAMs participate in this process. '06-'08 The initial attachment and "rolling" of leukocytes along the endothelium is mediated by selectins. The next stage involves firm attachment and is accomplished by a triggering event which causes activation of integrins thereby facilitating binding to their counter- receptors, the various members of the immunoglobulin gene superfamily zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA. The final stage, extravasation, involves a change in the shape of the leukocyte and transmigration through the endothelium. Thus, rather than being dependent on a single binding event, the specificity and diversity of leukocyte-endothelial cell interactions relies on sequential and combinatorial adhesive interactions. Given that HPC express a similar cohort of CAMs to those found on circulating ~ymp~0cytes20.22.24.38.&1 a similar scenario of events may be involved in the homing of HPC to the bone marrow (Figure 2). Since the marrow circulation is closed, in order to enter the marrow sinus extravascular compartment HPC must first recognise, or be recognised, by endothelial cells that separate the two compartments. Endothelial cells with this specialised function have yet to be identified. Once in the haemopoietic compartment, HPC interact with stromal elements that regulate their subsequent growth and development. It remains to be determined if the CAMs responsible for guiding HPC to the marrow endothelium are the same as those involved in binding to marrow stromal cells or whether distinct CAMs regulate the latter process of lodgement (Figure 2).

The mechanisms governing the release of primitive HPC from the bone marrow are unknown but may be distinct from the developmentally regulated changes in CAM expression that presumably contribute to the release of mature haemopoietic cells from the marrow. A variety of perturbations result in the transient release of primitive HPC into the peripheral circula-


MECHANISMS FOR LOCALISATION OF PROGENITORS IN MARROW zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA359 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA'LODGEMENT' zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAA STROMAL CELL

'NICHE

Figure 2 Hypothetical scheme illustrating the potential role of CAMs and their stromal ligands in the homing and lodgement of HPC to the bone marrow microenvironment. Selectins and Integrins are envisaged to participate in the homing of HPC to the marrow endothelium while other CAM-ligand pairs may contribute to their subsequent lodgement in the extravascular haemopoietic compartment. Alternatively, multiple CAM-ligand pairs may be required to promote adhesion of HPC to a specialised stromal cell niche. We speculate that in addition to mediating cell-cell adhesion, signals transduced following receptor-ligand binding may contribute directly to the regulation of HPC proliferation and development.

tion."' HGF are particularly effective in mobilizing HPC either as single agents or when used in combi- nation with other growth factors or cytotoxic chemotherapy. ' ' 1 *112 This observation is of considerable importance because of clinical interest in harvesting these cells for autologous transplantation. 110~113 It is likely that the variety of adhesive interactions between HPC and the marrow stroma reviewed herein play a major role in restricting HPC to the bone marrow under normal, steady state conditions. It therefore follows that movement of HPC from the marrow to the blood involves disruption of these adhesive interactions. The efficacy of HGF as 'mobilisers' may thus be explained (at least in part) by their well documented abilities to alter the expression and/or functional status of CAMs as described above. The phe- nomenon of mobilization is complex, involving multiple cell types and a variety of HGF (not simply those employed to initiate mobilization). Neverthe- less, while this hypothesis is almost certainly sim- plistic, it does provide a conceptual basis for the de- sign of studies to investigate the mechanism of mobilization. Such studies are in their infancy but should yield important clues in the future.

CONCLUSIONS AND FUTURE DIRECTIONS

Primitive human HPC exhibit an extensive array of CAMs, each of which interacts with specific ligands expressed by cells of the stromal microenvironment. CAMs expressed by HPC include members of the integrins, the selectins and the immunoglobulin gene superfamily . In documenting the expression and function of these CAMs we can begin to appreciate the true level of complexity of adhesive interactions that are involved in the regulation of normal haemopoiesis. Moreover, aberrant interaction between haemopoietic cells and stromal cells may contribute to the evolution and pathophysiology of a number of haemopoietic disorders including myeloid leukaemias and lymphoid malignancies .417114-117 While beyond the scope of this review, it is likely that the abnormal interactions observed in these diseases will be mediated through the modulation of one or more of the specific adhesive interactions described here.

A major objective for the future will be to under- stand the mechanisms that regulate CAM expression and function in HPC. In addition, it is clear that CAMs


360 P. J. SIMMONS zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAET zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAAL.

are signalling molecules. In the case of the integrins, for example, the signal transduction pathways share a number of features with those of polypeptide growth factors such as EGF, PDGF and insulin that bind to cell surface receptor tyrosine kinases. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAL18-12" More- over, a number of cell types including haemopoietic cells, demonstrate adhesion induced changes in gene e x p r e s ~ i o n . ~ ~ ~ ' ~ ~ Thus the diverse CAM-ligand interactions reviewed here, rather than simply serving to initiate zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBAand maintain contact between HPC and stromal cells, might also have an additional more direct role in controlling the growth and development of primitive haemopoietic cells as suggested by the 'niche' model (based on that of Schofield'22) depicted in Fig- ure 2. Such a model has obvious implications for the regulation of haemopoiesis, both normal and abnormal, and remains a provocative line of investigation for the future.

Acknowledgements The authors express their gratitude to Dr. Pri- tinder Kaur, Dr. Chris Juttner, and David Haylock for critically reviewing the manuscript. We also thank Silvanna Niutta and Sharon Paton for their excellent technical assistance in much of the ex- perimental work reported herein and to Mandy Huxtable for typing and preparation of the manuscript. This work was supported by grants from the National Health and Medical Research Council of Australia and the Anti-Cancer Foundation of the Universities of South Australia.

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Potential Adhesion Mechanisms for Localisation of Haemopoietic Progenitors to Bone Marrow Stroma

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