Abstract
Bone marrow stromal cells (BMSC) have gained increased attention because of their multipotency and adult stem cell character. They have been shown to differentiate into other cell types of the mesenchymal lineage and also into non-mesenchymal cells. The exact identity of the original cells, which are isolated from bone marrow by their selective adherence to plastic, remains unknown to date. We have established and characterized mouse BMSC cultures and analyzed three independent samples by cDNA microarrays. The expression profile was compared with two previous expression studies of human BMSC and revealed a high degree of concordance between different techniques and species. To gain clues about the positional context and biology of the isolated cells within the bone marrow stroma, we searched our data for genes that encode proteins of the extracellular matrix, cell adhesion proteins, cytoskeletal proteins and cytokines/cytokine receptors. This analysis revealed a close association of BMSC with vascular cells and indicated that BMSC resemble pericytes.
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References
Alliot F, Rutin J, Leenen PJ, Pessac B (1999) Pericytes and periendothelial cells of brain parenchyma vessels co-express aminopeptidase N, aminopeptidase A, and nestin. J Neurosci Res 58:367–378
Allt G, Lawrenson JG (2001) Pericytes: cell biology and pathology. Cell Tissue Organ 169:1–11
Balabanov R, Dore-Duffy P (1998) Role of the CNS microvascular pericyte in the blood-brain barrier. J Neurosci Res 53:637–644
Bianco P, Riminucci M, Gronthos S, Robey PG (2001) Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19:180–192
Brazelton TR, Rossi FM, Keshet GI, Blau HM (2000) From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290:1775–1779
Bruder SP, Jaiswal N, Haynesworth SE (1997) Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J Cell Biochem 64:278–294
Bruder SP, Kurth AA, Shea M, Hayes WC, Jaiswal N, Kadiyala S (1998) Bone regeneration by implantation of purified, culture-expanded human mesenchymal stem cells. J Orthop Res 16:155–162
Colter DC, Class R, DiGirolamo CM, Prockop DJ (2000) Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci 97:3213–3218
Colter DC, Sekiya I, Prockop DJ (2001) Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci USA 98:7841–7845
Deng W, Obrocka M, Fischer I, Prockop DJ (2001) In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Biophys Res Commun 282:148–52
Diaz-Flores L, Gutierrez R, Varela H, Rancel N, Valladares F (1991) Microvascular pericytes: a review of their morphological and functional characteristics. Histol Histopathol 6:269–86
Diaz-Flores L, Gutierrez R, Lopez-Alonso A, Gonzalez R, Varela H (1992) Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. Clin Orthop 275:280–286
Digirolamo CM, Stokes D, Colter D, Phinney DG, Class R, Prockop DJ (1999) Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagateand differentiate. Br J Haematol 107:275–281
Eglitis MA, Mezey E (1997) Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94:4080–4085
Ehler E, Karlhuber G, Bauer HC, Draeger A (1995) Heterogeneity of smooth muscle-associated proteins in mammalian brain microvasculature. Cell Tissue Res 279:393–403
Erickson AC, Couchman JR (2000) Still more complexity in mammalian basement membranes. J Histochem Cytochem 48:1291–1306
Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279:1528–1530
Friedenstein AJ, et al (1976) Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 4:267–274
Galmiche MC, Koteliansky VE, Briere J, Herve P, Charbord P (1993) Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway. Blood 82:66–76
Gerhardt H, Wolburg H, Redies C (2000) N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn 218:472–479
Goshima J, Goldberg VM, Caplan AI (1991) Osteogenic potential of culture-expanded rat marrow cells as assayed in vivo with porous calcium phosphate ceramic. Biomaterials 12:253–258
Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, Mulligan RC (1999) Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401:390–394
Haselton FR, Heimark RL (1997) Role of cadherins 5 and 13 in the aortic endothelial barrier. J Cell Physiol 171:243–251
Hellstrom M, Kaln M, Lindahl P, Abramsson A, Betsholtz C (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055
Hirschi KK, D'Amore PA (1996) Pericytes in the microvasculature. Cardiovasc Res 32:687-698
Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313
Jia L, Young MF, Powell J, Yang L, Ho NC, Hotchkiss R, Robey PG, Francomano CA (2002) Gene expression profile of human bone marrow stromal cells: high-throughput expressed sequence tag sequencing analysis. Genomics 79:7–17
Kadiyala S, Young RG, Thiede MA, Bruder SP (1997) Culture expanded canine mesenchymal stem cells possess osteochondrogenic potential in vivo and in vitro. Cell Transplant 6:125–134
Kon E, Muraglia A, Corsi A, Bianco P, Marcacci M, Martin I, Boyde A, Ruspantini I, Chistolini P, Rocca M, Giardino R, Cancedda R, Quarto R (2000) Autologous bone marrow stromal cells loaded onto porous hydroxyapatite ceramic accelerate bone repair in critical-size defects of sheep long bones. J Biomed Mater Res 49:328–337
Kopen GC, Prockop DJ, Phinney DG (1999) Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 96:10711–10716
Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC, Fine A (2001) Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 128:5181–5188
Krebsbach PH, Kuznetsov SA, Satomura K, Emmons RV, Rowe DW, Robey PG (1997) Bone formation in vivo: comparison of osteogenesis by transplanted mouse and human marrow stromal fibroblasts. Transplantation 63:1059–1069
Kuznetsov SA, Friedenstein AJ, Robey PG (1997) Factors required for bone marrow stromal fibroblast colony formation in vitro. Br J Haematol 97:561–570
Kuznetsov SA, Mankani MH, Robey PG (2000) Effect of serum on human bone marrow stromal cells: ex vivo expansion and in vivo bone formation. Transplantation 70:1780–1787
Lapidot T (2001) Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice. The role of SDF-1/CXCR4. Ann N Y Acad Sci 938:83–95
Li J, Sensebe L, Herve P, Charbord P (1995) Nontransformed colony-derived stromal cell lines from normal human marrows. II. Phenotypic characterization and differentiation pathway. Exp Hematol 23:133–141
Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705
Mets T, Verdonk G (1981) Variations in the stromal cell population of human bone marrow during aging. Mech Ageing Dev 15:41–49
Nehls V, Drenckhahn D (1991) Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J Cell Biol 113:147–154
Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705
Pablos JL, Amara A, Bouloc A, Santiago B, Caruz A, Galindo M, Delaunay T, Virelizier JL, Arenzana-Seisdedos F (1999) Stromal-cell derived factor is expressed by dendritic cells and endothelium in human skin. Am J Pathol 155:1577–1586
Pereira RF, Halford KW, O'Hara MD, Leeper DB, Sokolov BP, Pollard MD, Bagasra O, Prockop DJ (1995) Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. Proc Natl Acad Sci USA 92:4857–4861
Pereira RF, O'Hara MD, Laptev AV, Halford KW, Pollard MD, Class R, Simon D, Livezey K, Prockop DJ (1998) Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci USA 95:1142–1147
Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170
Phinney DG, Kopen G, Isaacson RL, Prockop DJ (1999) Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation. J Cell Biochem 72:570–585
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147
Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276:71–74
Reyes M, Verfaillie CM (2001) Characterization of multipotent adult progenitor cells, a subpopulation of mesenchymal stem cells. Ann N Y Acad Sci 938:231–233
Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie CM (2001) Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98:2615–2625
Richardson RL, Hausman GJ, Campion DR (1982) Response of pericytes to thermal lesion in the inguinal fat pad of 10-day-old rats. Acta Anat 114:41–57
Rohm B, Ottemeyer A, Lohrum M, Puschel AW (2000) Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A. Mech Dev 93:95–104
Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR (2000) Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164:247–256
Satoh M, Mioh H, Shiotsu Y, Ogawa Y, Tamaoki T (1997) Mouse bone marrow stromal cell line MC3T3-G2/PA6 with hematopoietic-supporting activity expresses high levels of stem cell antigen Sca-1. Exp Hematol 25:972–979
Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, Lenvik T, Johnson S, Hu WS, Verfaillie CM (2002) Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 109:1291–1302
Shepro D, Morel NM (1993) Pericyte physiology. FASEB J 7:1031–1038
Sincock PM, Mayrhofer G, Ashman LK (1997) Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissues: comparison with CD9, CD63, and alpha5beta1 integrin. J Histochem Cytochem 45:515–525
Sincock PM, Fitter S, Parton RG, Berndt MC, Gamble JR, Ashman LK (1999) PETA-3/CD151, a member of the transmembrane 4 superfamily, is localised to the plasma membrane and endocytic system of endothelial cells, associates multiple integrins and modulates cell function. J Cell Sci 112:833–844
Soker S (2001) Neuropilin in the midst of cell migration and retraction. Int J Biochem Cell Biol 33:433–437
Tamaki S, Wada H, Ohfuzi K, Shibata T, Masuya M, Kageyama S, Gabazza EC, Kawakami K, Tsuji K, Miyanishi E, Minami N, Nobori T, Shiku H (2002) Hemostatic abnormalities following bone marrow transplantation. Clin Appl Thromb Hemost 8:125–132
Taraszka KS, Higgins JM, Tan K, Mandelbrot DA, Wang JH, Brenner MB (2000) Molecular basis for leukocyte integrin alpha(E)beta(7) adhesion to epithelial (E)-cadherin. J Exp Med 191:1555–1567
Theele DP, Streit WJ (1993) A chronicle of microglial ontogeny. Glia 7:5–8
Thomas WE (1999) Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Brain Res Rev 31:42–57
Tremain N, Korkko J, Ibberson D, Kopen GC, DiGirolamo C, Phinney DG (2001) MicroSAGE analysis of 2,353 expressed genes in a single cell-derived colony of undifferentiated human mesenchymal stem cells reveals mRNAs of multiple cell lineages. Stem Cells 19:408–418
Verbeek MM, Otte-Holler I, Ruiter DJ, Waal RM de (1999) Human brain pericytes as a model system to study the pathogenesis of cerebrovascular amyloidosis in Alzheimer's disease. Cell Mol Biol (Noisy-le-grand) 45:37–46
Wakitani S, Saito T, Caplan AI (1995) Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18:1417–1426
Wegiel J, Wisniewski HM (1992) Tubuloreticular structures in microglial cells, pericytes and endothelial cells in Alzheimer's disease. Acta Neuropathol (Berl) 83:653–658
Welm BE, Tepera SB, Venezia T, Graubert TA, Rosen JM, Goodell MA (2002) Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 245:42–56
Whetton AD, Graham GJ (1999) Homing and mobilization in the stem cell niche. Trends Cell Biol 9:233–238
Wisniewski HM, Wegiel J, Wang KC, Lach B (1992) Ultrastructural studies of the cells forming amyloid in the cortical vessel wall in Alzheimer's disease. Acta Neuropathol (Berl) 84:117–127
Wolf NS (1999) The hematopoietic microenvironment: stromal cell types: characterization and function in situ and in vitro. Hematology 4:241–254
Woodbury D, Schwarz EJ, Prockop DJ, Black IB (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61:364–370
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We thank Ulf Gurok and Rogier Versteeg for critically reading the manuscript and Bettina Lipkowitz for excellent technical support. We also acknowledge the help of Tobias Müller in implementing the EM algorithm.
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This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 577, Teilprojekt C3)
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Wieczorek, G., Steinhoff, C., Schulz, R. et al. Gene expression profile of mouse bone marrow stromal cells determined by cDNA microarray analysis. Cell Tissue Res 311, 227–237 (2003). https://doi.org/10.1007/s00441-002-0671-3
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DOI: https://doi.org/10.1007/s00441-002-0671-3