Abstract
CD34, podocalyxin, and endoglycan are members of a family of single-pass transmembrane proteins that show distinct expression on early hematopoietic precursors and vascular-associated tissue. In spite of the fact that the expression of CD34 on these early progenitors has been known for over 20 yr and used clinically in hematopoietic stem cell transplantation for more than 15 yr, little is known about its exact role or function. More recently, CD34 expression has been shown to distinguish activated early progenitors from quiescent cells. With the subsequent identification of podocalyxin and endoglycan as related family members also expressed on early progenitor cells, attention is slowly shifting toward understanding how these molecules might contribute to progenitor function and behavior. In this review we examine the existing evidence and propose testable models to reveal the importance of these molecules for stem and progenitor cell function.
Similar content being viewed by others
References
Sassetti C, Van Zante A, Rosen SD: Identification of endoglycan, a member of the CD34/podocalyxin family of sialomucins. J Biol Chem 2000;275: 9001–9010.
Doyonnas R, Kershaw DB, Duhme C, et al: Anuria, omphalocele, and perinatal lethality in mice lacking the CD34-related protein podocalyxin. J Exp Med 2001; 194:13–27.
Nielsen JS, Doyonnas R, McNagny KM: Avian models to study the transcriptional control of hematopoitic lineage commitment and to identify lineage-specific genes. Cells Tissues Organs 2002;171:44–63.
Li J, Li Y, Brophy PD, Kershawt DB: Gene structure and alternative splicing of murine podocalyxin: a member of the CD34 sialomucin family. DNA Seq 2001;12:407–412.
Krause DS, Ito T, Fackler MJ, et al: Characterization of murine CD34, a marker for hematopoietic progenitor and stem cells. Blood 1994;84:691–701.
Kerjaschki D, Sharkey DJ, Farquhar MG: Identification and characterization of podocalyxin—the major sialoprotein of the renal glomerular epithelial cell. J Cell Biol 1984;98:1591–1596.
Sutherland DR, Watt SM, Dowden G, et al: Structural and partial amino acid sequence analysis of the human hemopoietic progenitor cell antigen CD34. Leukemia 1988;2:793–803.
Hemmerich S, Butcher EC, Rosen SD: Sulfation-dependent recognition of high endothelial venules (HEV)-ligands by L-selectin and MECA 79, adhesion-blocking monoclonal antibody. J Exp Med 1994;80; 2219–2226.
Bistrup A, Bhakta S, Lee JK, et al: Sulfotransferases of two specificities function in the reconstitution of high endothelial cell ligands for L-selectin. J Cell Biol 1999;145:899–910.
Fieger CB, Sassetti CM, Rosen SD: Endoglycan, a member of the CD34 family, functions as an L-selectin ligand through modification with tyrosine sulfation and sialyl Lewis x. J Biol Chem 2003;278:27390–27398.
Baumhueter S, Singer MS, Henzel W, et al: Binding of L-selectin to the vascular sialomucin CD34. Science 1993;262:436–438.
Sassetti C, Tangemann K, Singer MS, Kreshaw DB, Rosen SD: Identification of podocalyxin-like protein as a high endothelial venule ligand for L-selectin: parallels to CD34. J Exp Med 1998;187:1965–1975.
Paavonen T, Renkonen R: Selective expression of sialyl-Lewis x and Lewis a epitopes, putative ligands for L-selectin, on peripheral lymph-node high endothelial venules. Am J Pathol 1992;141:1259–1264.
Mitsuoka C, Sawada-Kasugai M, Ando-Furui K, et al: Identification of a major carbohydrate capping group of the L-selectin ligand on high endothelial venules in human lymph nodes as 6-sulfo sialyl Lewis X. J Biol Chem 1998;273:11225–11233.
Mitsuoka C, Kawakami-Kimura N, Kasugai-Sawada M, et al: Sulfated sialyl Lewis X, the putative L-selectin ligand, detected on endothelial cells of high endothelial venules by a distinct set of anti-sialyl Lewis X antibodies. Biochem Biophys Res Commun 1997;230:546–551.
Takeda T, Go WY, Orlando RA, Farquhar MG: Expression of podocalyxin inhibits cell-cell adhesion and modifies junctional properties in Madin-Darby canine kidney cells. Mol Biol Cell 2000;11:3219–3232.
Fackler MJ, Civin CI, Sutherland DR, Baker MA, May WS: Activated protein kinase C directly phosphorylates the CD34 antigen on hematopoietic cells. J Biol Chem 1990;265:11056–11061.
Fackler MJ, Civin CI, May WS: Up-regulation of surface CD34 is associated with protein kinase C-mediated hyperphosphorylation of CD34. J Biol Chem 1992;267:17540–17546.
Felschow DM, McVeigh ML, Hoehn GT, Civin CI, Fackler MJ: The adapter protein CrkL associates with CD34. Blood 2001;97:3768–3775.
Li Y, Li J, Straight SW, Kershaw DB: PDZ domainmediated interaction of rabbit podocalyxin and Na(+)/H(+) exchange regulatory factor-2. Am J Physiol Renal Physiol 2002;282:F1129–1139.
Meder D, Shevchenko A, Simons K, Fullekrug J: Gp135/podocalyxin and NHERF-2 participate in the formation of a preapical domain during polarization of MDCK cells. J Cell Biol 2005;168:303–313.
Schmieder S, Nagai M, Orlando RA, Takeda T, Farquhar MG: Podocalyxin activates RhoA and induces actin reorganization through NHERF1 and Ezrin in MDCK cells. J Am Soc Nephrol 2004;15:2289–2298.
Takeda T: Podocyte cytoskeleton is connected to the integral membrane protein podocalyxin through Na+/H+-exchanger regulatory factor 2 and ezrin. Clin Exp Nephrol 2003;7:260–269.
Takada T, McQuistan T, Orlando RA, Farquhar MG: Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton. J Clin Invest 2001;108:289–301.
Tan PC, Furness SGB, Merkens H, et al: NHERF-1 is an hematopoietic ligand for a subset of the CD34 family of stem cell surface proteins. Stem Cells 2005 16;Epub Jan 12
Civin CI, Strauss LC, Brovall C, Fackler MJ, Schwartz JF, Shaper JH: Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. J Immunol 1984;133:157–165.
Andrews RG, Singer JW, Bernstein ID: Monoclonal antibody 12-8 recognizes a 115-kd molecule present on both unipotent and multipotent hematopoietic colonyforming cellsq and their precursors. Blood 1986; 67:842–845.
Katz FE, Tindle R, Sutherland DR, Greaves MF: Identification of a membrane glycoprotein associated with haemopoietic progenitor cells. Leuk Res 1985;9: 191–198.
Berenson RJ, Andrews RG, Bensinger WI, et al: Antigen CD34+ marrow cells engraft lethally irradiated baboons. J Clin Invest 1988;81:951–955.
Berenson RJ, Bensinger WI, Hill RS, et al: Engraftment after infusion of CD34+ marrow cells in patients with breast cancer or neuroblastoma. Blood 1991;77:1717–1722.
Baumhueter S, Dybdal N, Kyle C, Lasky LA: Global vascular expression of murine CD34, a sialomucin-like endothelial ligand for L-selectin. Blood 1994;84: 2554–2565.
Kalaria RN, Kroon SN: Expression of leukocyte antigen CD34 by brain capillaries in Alzheimer's disease and neurologically normal subjects. Acta Neuropathol (Berl) 1992;84:606–612.
Fina L, Molgaard HV, Robertson D, et al: Expression of the CD34 gene in vascular endothelial cells. Blood 1990;75:2417–2426.
Lin G, Finger E, Gutierrerz-Ramos JC: Expression of CD34 in endothelial cells, hematopoietic progenitors and nervous cells in fetal and adult mouse tissues. Eur J Immunol 1995;25:1508–1516.
Young PE, Baumhueter S, Lasky LA: The sialomucin CD34 is expressed on hematopoietic cells and blood vessels during murine development. Blood 1995;85: 96–105.
Wood HB, May G, Healy L, Enver T, Morriss-Kay GM: CD34 expression patterns during early mouse development are related to modes of blood vessel formation and reveal additional sites of hematopoiesis. Blood 1997;90:2300–2311.
Fennie C, Cheng J, Dowbenko D, Young P, Lasky LA: CD34+ endothelial cell lines derived from murine yolk sac induce the proliferation and differentiation of yolk sac CD34+ hematopoietic progenitors. Blood 1995; 86:4454–4467.
Tavian M, Coulombel L, Luton D, Clemente HS, Dieterlen-Lievre F, Peault B: Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 1996;87:67–72.
Ohneda O, Fennie C, Zheng Z, et al: Hematopoietic stem cell maintenance and differentiation are supported by embryonic aorta-gonad-mesonephros regionderived endothelium. Blood 1998;92:908–919.
Oostendorp RA, Harvey KN, Kusadasi N, et al: Stromal cell lines from mouse aorta-gonads-mesonephros subregions are potent supporters of hematopoietic stem cell activity. Blood 2002;99:1183–1189.
Nakayama H, Enzan H, Miyazaki E, Kuroda N, Naruse K, Hiroi M: Differential expression of CD34 in normal colorectal tissue, peritumoral inflammatory tissue, and tumour stroma. J Clin Pathol 2000;53:626–629.
Delia D, Lampugnani MG, Resnati M, et al: CD34 expression is regulated reciprocally with adhesion molecules in vascular endothelial cells in vitro. Blood 1993;81:1001–1008.
Panepucci RA, Siufi JL, Silva WA, Jr, et al: Comparison of gene expression of umbilical cord vein and bone marrow-derived mesenchymal stem cells. Stem Cells 2004;22:1263–1278.
Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ: Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 2004;103:1662–1668.
Simmons PJ, Torok-Storb B: CD34 expression by stromal precursors in normal human adult bone marrow. Blood 1991;78:2848–2853.
Lee JY, Qu-Petersen Z, Cao B, et al: Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. J Cell Biol 2000; 150:1085–1100.
Garcia-Pacheco JM, Oliver C, Kimatrai M, Blanco FJ, Olivares EG: Human decidual stromal cells express CD34 and STRO-1 and are related to bone marrow stromal precursors. Mol Hum Reprod 2001;7:1151–1157.
Goan SR, Junghahn I, Wissler M, et al: Donor stromal cells from human blood engraft in NOD/SCID mice. Blood 2000;96:3971–3978.
Hung SC, Chen NJ, Hsieh SL, Li H, Ma HL, Lo WH: Isolation and characterization of size-sieved stem cells from human bone marrow. Stem Cells 2002;20:249–258.
Krause DS, Fackler MJ, Civin CI, May WS: CD34: structure, biology, and clinical utility. Blood 1996;87: 1–13.
Jones RJ, Collector MI, Barber JP, et al: Characterization of mouse lymphohematopoietic stem cells lacking spleen colony-forming activity. Blood 1996;88:487–491.
Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC: Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996;183:1797–1806.
Osawa M, Hanada K, Hamada H, Nakauchi H: Longterm lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 1996;273:242–245.
Goodell MA, Rosenzweig M, Kim H, et al: Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 1997;3:1337–1345.
Bhatia M, Bonnet D, Murdoch B, Gan OI, Dick JE: A newly discovered class of human hematopoietic cells with SCID-repopulating activity. Nat Med 1998;4: 1038–1045.
Zanjani ED, Almeida-Porada G, Livingston AG, Flake AW, Ogawa M. Human bone marrow CD34-cells engraft in vivo and undergo multilineage expression that includes giving rise to CD34+cells. Exp Hematol 1998;26:353–360.
Sutherland DR, Abdullah KM, Cyopick P, Mellors A: Cleavage of the cell-surface O-sialoglycoproteins CD34, CD43, CD44, and CD45 by a novel glycoprotease from Pasteurella haemolytica. J Immunol 1992; 148:1458–1464.
Donnelly DS, Zelterman D, Sharkis S, Krause DS: Functional activity of murine CD34+ and CD34−hematopoietic stem cell populations. Exp Hematol 1999;27:788–796.
Morel F, Galy A, Chen B, Szilvassy SJ: Equal distribution of competitive long-term repopulating stem cells in the CD34+ and CD34− fractions of Thy-llowLin-/lowSca-1+bone marrow cells. Exp Hematol 1998;26:440–448.
Morel F, Szilvassy SJ, Travis M, Chen B, Galy A: Primitive hematopoietic cells in murine bone marrow express the CD34 antigen. Blood 1996;88:3774–3784.
Sutherland DR, Stewart AK, Keating A: CD34 antigen: molecular features and potential clinical applications. Stem Cells 11 Suppl 1993;3:50–57.
Sato T, Laver JH, Ogawa M: Reversible expression of CD34 by murine hematopoietic stem cells. Blood 1999;94:2548–2554.
Zanjani ED, Almeida-Porada G, Livingston AG, Zeng H, Ogawa M: Reversible expression of CD34 by adult human bone marrow long-term engrafting hematopoietic stem cells. Exp Hematol 2003;31:406–412.
Dao MA, Arevalo J, Nolta JA: Reversibility of CD34 expression on human hematopoietic stem cells that retain the capacity for secondary reconstitution Blood 2003;101:112–118.
Tajima F, Sato T, Laver JH, Ogawa M: CD34 expression by murine hematopoietic stem cells mobilized by granulocyte colony-stimulating factor. Blood 2000;96: 1989–1993.
Ogawa M, Tajima F, Ito T, Sato T, Laver JH, Deguchi T: CD34 expression by murine hematopoietic stem cells. Developmental changes and kinetic alterations. Ann NY Acad Sci 2001;938:139–145.
Dooley DC, Oppenlander BK, Xiao M: Analysis of primitive CD34− and CD34+ hematopoietic cells from adults: gain and loss of CD34 antigen by undifferentiated cells are closely linked to proliferative status in culture. Stem Cells 2004;22:556–569.
Roberts AW, Metcalf D: Noncycling state of peripheral blood progenitor cells mobilized by granulocyte colony-stimulating factor and other cytokines. Blood 1995;86:1600–1605.
Uchida N, He D, Friera AM, et al: The unexpected G0/G1 cell cycle status of mobilized hematopoietic stem cells from peripheral blood. Blood 1997;89: 465–472.
Moore MA, Metcalf D: Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol 1970;18:279–296.
Sanchez MJ, Holmes A, Miles C, Dzierzak E: Characterization of the first definitive hematopoietic stem cells in the AGM and liver of the mouse embryo. Immunity 1996;5:513–525.
McClanahan T, Dalrymple S, Barkett M, Lee F: Hematopoietic growth factor receptor genes as markers of lineage commitment during in vitro development of hematopoietic cells. Blood 1993;81:2903–2915.
Johnson GR, Jones RO: Differentiation of the mammalian hepatic primordium in vitro. I. Morphogenesis and the onset of haematopoiesis. J Embryol Exp Morphol 1973;30:83–96.
Papayannopoulou T, Brice M, Broudy VC, Zsebo KM: Isolation of c-kit receptor-expressing cells from bone marrow, peripheral blood, and fetal liver: functional properties and composite antigenic profile. Blood 1991;78:1403–1412.
Abe J: Immunocytochemical characterization of lymphocyte development in human embryonic and fetal livers. Clin Immunol Immunopathol 1989;51:13–21.
Drew E, Merkens H, Chelliah S, Doyonnas R, McNagny KM: CD34 is a specific marker of mature murine mast cells. Exp Hematol 2002;30:1211.
Rottem M, Okada T, Goff JP, Metcalfe DD: Mast cells cultured from the peripheral blood of normal donors and patients with mastocytosis originate from a CD34+/Fc epsilon RI-cell population. Blood 1994;84:2489–2496.
Welker P, Grabbe J, Zuberbier T, Guhl S, Henz BM: Mast cell and myeloid marker expression during early in vitro mast cell differentiation from human peripheral blood mononuclear cells. J Invest Dermatol 2000;114: 44–50.
Krauth MT, Majlesi Y, Florian S, et al: Cell surface membrane antigen phenotype of human gastrointestinal mast cells. Int Arch Allergy Immunol 2005;138: 111–120.
Drew E, Huettner CS, Tenen DG, McNagny KM: CD34 expression by mast cells: of mice and men. Blood 2005;106:1885–1887.
Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD: Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13) Blood 1999;94:2333–2342.
Chen CC, Grimbaldeston MA, Tsai M, Weissman IL, Galli SJ: Identification of mast cell progenitors in adult mice. Proc Natl Acad Sci USA 2005;102:11408–11413.
Terstappen LW, Huang S, Picker LJ: Flow cytometric assessment of human T-cell differentiation in thymus and bone marrow. Blood 1992;79:666–677.
Baines P, Mayani H, Bains M, Fisher J, Hoy T, Jacobs A: Enrichment of CD34 (My 10)-positive myeloid and erythroid progenitors from human marrow and their growth in cultures supplemented with recombinant human granulocyte-macrophage colony-stimulating factor. Exp Hematol 1988:16:785–789.
Fackler MJ, Krause DS, Smith OM, Civin CI, May WS: Full-length but not truncated CD34 inhibits hematopoietic cell differentiation of M1 cells. Blood 1995; 85:3040–3047.
Cheng J, Baumhueter S, Cacalano G, Carver-Moore K, Thibodeaux H, Thomas R, Broxmeyer HE, Cooper S, Hague N, Moore M, Lasky LA: Hematopoietic defects in mice lacking the sialomucin CD34. Blood 1996;87:479–490.
Satomaa T, Renkonen O, Helin J, Kirveskari J, Makitie A, Renkonen R: O-glycans on human high endothelial CD34 putatively participating in L-selectin recognition. Blood 2002;99:2609–2611.
Puri KD, Finger EB, Gaudernack G, Springer TA: Sialomucin CD34 is the major L-selectin ligand in human tonsil high endothelial venules. J Cell Biol 1995;131:261–270.
Suzuki A, Andrew DP, Gonzalo JA, et al: CD34-deficient mice have reduced eosinophil accumulation after allergen exposure and show a novel crossreactive 90-kD protein. Blood 1996;87:3550–3562.
Blom N, Gammeltoft S, Brunak S: Sequence and structure-based prediction of eukaryotic protein phosphorylation sites. J Mol Biol 1999;294:1351–1362.
Blom N, Sicheritz-Ponten T, Gupta R, Gammeltoft S, Brunak S: Prediction of post-translational glycosylation and prosphorylation of proteins from the amino acid sequence. Proteomics 2004;4:1633–1649.
Rush J, Moritz A, Lee KA, et al: Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nat Biotechnol 2005;23:94–101.
Lanza F, Healy L, Sutherland DR: Structural and functional features of the CD34 antigen: an update. J Biol Regul Homeost Agents 2001;15:1–13.
Tada J, Omine M, Suda T, Yamaguchi N: A common signaling pathway via Syk and Lyn tyrosine kinases generated from capping of the sialomucins CD34 and CD43 in immature hematopoietic cells. Blood 1999; 93:3723–3735.
Majdic O, Stockl J, Pickl WF, et al: Signaling and induction of enhanced cytoadhesiveness via the hematopoietic progenitor cell surface molecule CD34. Blood 1994;83:1226–1234.
Hu MC, Chien SL: The cytoplasmic domain of stem cell antigen CD34 is essential for cytoadhesion signaling but not sufficient for proliferation signaling. Blood 1998;91:1152–1162.
Healy L, May G, Gale K, Grosveld F, Greaves M, Enver T: The stem cell antigen CD34 functions as a regulator of hemopoietic cell adhesion. Proc Natl Acad Sci USA 1995;92:12240–12244.
Drew E, Merzaban JS, Seo W, Ziltener HJ, McNagny KM: CD34 and CD43 inhibit mast cell adhesion and are required for optimal mast cell reconstitution. Immunity 2005;22:43–57.
Doyonnas R, Nielsen JS, Chelliah S, et al: Podocalyxin is a CD34-related marker of murine hematopoietic stem cells and embryonic erythroid cells. Blood 2005;105: 4170–4178.
McNagny KM, Pettersson I, Rossi F, et al: Thrombomucin, a novel cell surface protein that defines thrombocytes and multipotent hematopoietic progenitors. J Cell Biol 1997;138:1395–1407.
Hara T, Nakano Y, Tanaka M, et al: Identification of podocalyxin-like protein 1 as a novel cell surface marker for hemangioblasts in the murine aortagonad-mesonephros region. Immunity 1999;11: 567–578.
Horvat R, Hovorka A, Dekan G, Poczewski H, Kerjaschki D: Endothelial cell membranes contain podocalyxin—the major sialoprotein of visceral glomerular epithelial cells. J Cell Biol 1986;102:484–491.
Schnabel E, Dekan G, Miettinen A, Farquhar MG: Biogenesis of podocalyxin—the major glomerular sialoglycoprotein—in the newborn rat kidney. Eur J Cell Biol 1989;48:313–326.
Vitureira N, McNagny K, Soriano E, Burgaya F: Pattern of expression of the podocalyxin gene in the mouse brain during development. Gene Expr Patterns 2005;5:349–354.
McNagny KM, Lim F, Grieser S, Graf T: Cell surface proteins of chicken hematopoietic progenitors, thrombocytes and eosinophils detected by novel monoclonal antibodies. Leukemia 1992;6:975–984.
Graf T, McNagny K, Brady G, Frampton J: Chicken “erythroid” cells transformed by the Gag-Myb-Etsencoding E26 leukemia virus are multipotent. Cell 1992;70:201–213.
Kerosuo L, Juvonen E, Alitalo R, Gylling M, Kerjaschki D, Miettinen A: Podocalyxin in human haematopoietic cells. Br J Haematol 2004;124:809–818.
Miettinen A, Solin ML, Reivinen J, Juvonen E, Vaisanen R, Holthofer H: Podocalyxin in rat platelets and megakaryocytes. Am J Pathol 1999;154:813–822.
Kerjaschki D, Vernillo AT, Farquhar MG: Reduced sialylation of podocalyxin—the major sialoprotein of the rat kidney glomerulus—in aminonucleoside nephrosis. Am J Pathol 1985;118:343–349.
Seiler MW, Rennke HG, Venkatachalam MA, Cotran RS: Pathogenesis of polycation-induced alterations (“fusion”) of glomerular epithelium. Lab Invest 1977;36:48–61.
Seiler MW, Venkatachalam MA, Cotran RS: Glomerular epithelium: structural alterations induced by polycations. Science 1975;189:390–393.
Voltz JW, Weinman EJ, Shenolikar S: Expanding the role of NHERF, a PDZ-domain containing protein adapter, to growth regulation. Oncogene 2001;20: 6309–6314.
Louvet-Vallee S: ERM proteins: from cellular architecture to cell signaling. Biol Cell 2000;92:305–316.
Ivetic A, Ridley AJ: Ezrin/radixin/moesin proteins and Rho GTPase signalling in leucocytes. Immunology 2004;112:165–176.
Sarangapani KK, Yago T, Klopocki AG, et al: Low force decelerates L-selectin dissociation from P-selectin glycoprotein ligand-1 and endoglycan. J Biol Chem 2004;279:2291–2298.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Furness, S.G.B., McNagny, K. Beyond mere markers. Immunol Res 34, 13–32 (2006). https://doi.org/10.1385/IR:34:1:13
Issue Date:
DOI: https://doi.org/10.1385/IR:34:1:13