Abstract
Mammalian bone marrow contains mesenchymal lineage progenitors that have high proliferative capacity, are clonogenic in vitro, and demonstrate the ability to differentiate to multiple mesenchymal lineage tissue types, including bone, cartilage, fat, smooth muscle, and cardiac muscle. Isolation of these cells on the basis of their physical properties results in clonal outgrowth with functional in vitro heterogeneity. Prospective immunoselection of mesenchymal lineage precursor cells enhances reproducible functional outgrowth, and the phenotype STRO-1brightVCAM-1+ characterizes a multipotent mesenchymal precursor cell in vivo, which gives rise to a 50% frequency of multipotential clonal outgrowth in vitro. These cells are anatomically located in perivascular niches in the bone marrow and throughout the body and demonstrate phenotypic and genetic identity to vascular pericytes. Consistent with the pivotal role played by pericytes in formation of vascular structures during embryogenesis, cumulative data show that mesenchymal precursors regulate adult vasculature formation. In addition, under appropriate differentiation conditions, mesenchymal precursors give rise to new cardiomyocytes. Because vascular network formation is a prerequisite for long-term survival of cardiomyocyte precursors implanted into ischemic myocardium, mesenchymal lineage precursors appear to be ideal candidates for enhancing both cardiac neovascularization and myogenesis. Clinical protocols using these cells will require optimization of serum-free culture methodologies and biological scaffolds/matrices for enhancing survival of implanted cells. Finally, recent data indicating that mesenchymal lineage precursors evade immune recognition raise the exciting prospect that allogeneic use of these cells may be feasible.
Key Words
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
REFERENCES
Friedenstein AJ, Chailakhyan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea pig bone marrow and spleen cells. Cell Tissue Kinet 1970;3:393–402.
Gronthos S, Simmons PJ. The growth factor requirements of STRO-1-positive human bone marrow stromal precursors under serum-deprived conditions in vitro. Blood 1995;85:929–940.
Kuznetsov SA, Krebsbach PH, Satomura K, et al. Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J Bone Miner Res 1997;12:1335–1347.
Satomura K, Krebsbach P, Bianco P, et al. Osteogenic imprinting upstream of marrow stromal cell differentiation. J Cell Biochem 2000;78:391–403.
Friedenstein AJ, Latzinik NW, Grosheva AG, et al. Marrowmicroenvironment transfer by heterotopic transplantation of freshly isolated and cultured cells in porous sponges. Exp Hematol 1982;10:217–227.
Ashton BA, Allen TD, Howlett CR, et al. Formation of bone and cartilage by marrow stromal cells in diffusion chambers in vivo. Clin Orthop 1980;151:294–307.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147.
Simmons PJ, Torok-Storb B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood 1991;78:55–62.
Haynesworth SE, Baber MA, Caplan AI. Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. Bone 1992;13:.
Joyner CJ, Bennett A, Triffitt JT. Identification and enrichment of human osteoprogenitor cells by using differentiation stage-specific monoclonal antibodies. Bone 1997;21:1–6.
Gronthos S, Graves SE, Ohta S, et al. The STRO-1+ fraction of adult human bone marrow contains the osteogenic precursors. Blood 1994;84:4164–4173.
Simmons PJ, Torok-Storb B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood 1991;78:55–62.
Gronthos S, Simmons PJ. The biology and application of human bone marrow stromal cell precursors. J Hematother 1996;5:15–23.
Simmons PJ, Gronthos S, Zannettino A, et al. Isolation, characterization and functional activity of human marrow stromal progenitors in hemopoiesis. Prog Clin Biol Res 1994;389:271–280.
Filshie RJ, Zannettino AC, Makrynikola V, et al. MUC18, a member of the immunoglobulin superfamily, is expressed on bone marrow fibroblasts and a subset of hematological malignancies. Leukemia 1998;12:414–421.
Gronthos S, Mankani M, Brahim J, et al. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA 2000;97:13,625–13,630.
Gronthos S, Zannettino AC, Hay SJ, et al. Molecular and cellular characterisation of highly purified stromal stems derived from human bone marrow. J Cell Sci 2003;116:1827–1835.
Shi S, Gronthos S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res 2003;18:696–704.
Galmiche MC, Koteliansky VE, Briere J, Herve P, Charbord P. Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway. Blood 1993;82:66–76.
Schor AM, Canfield AE. Osteogenic potential of vascular pericytes. In: Beresford JN, Owen ME, eds. Marrow Stromal Cell Culture. Cambridge University Press, Cambridge, UK, 1998, pp. 28–148.
Zuckerman KS, Wicha MS. Extracellular matrix production by the adherent cells of long-term murine bone marrow cultures. Blood 1983;61:540–547.
Gronthos S, Simmons PJ. The growth factor requirements of STRO-1+ human bone marrow stromal precursors under serum-deprived conditions. Blood 1995;85:929–940.
Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C. 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 1999;126:3047–3055.
Schor AM, Canfield AE, Sutton AB, Arciniegas E, Allen TD. Pericyte differentiation. Clin Orthop 1995;313:81–91.
Sims DE. The pericyte—a review. Tissue Cell 1986;18:153–174.
Diaz-Flores L, Gutiérrez R, Gonzales P, Varela H. Inducible perivascular cells contribute to the neochondrogenesis in grafted perichondrium. Anat Rec 1991;229:1–8.
Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE. Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 1998;13:828–838.
Doherty MJ, Canfield AE. Gene expression during vascular pericyte differentiation. Crit Rev Eukaryot Gene Exp 1999;9:1–17.
Brighton CT, Lorich DG, Kupcha R, Reilly TM, Jones AR, Woodbury, 2nd, RA. The pericyte as a possible osteoblast progenitor cell. Clin Orthop 1992;275:287–299.
Tavian M, Coulombel L, Luton D, San Clemente H, Dieterlen-Lievre F, Peault B. Aorta-associated CD34 hematopoietic cells in the early human embryo. Blood 1996;87:67–72.
Jaffredo T, Gautier R, Eichmann A, Dieterlen-Lievre F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 1998;125:4575–4583.
Drake CJ, Hungerford JE, Little CD. Morphogenesis of the first blood vessels. Ann NY Acad Sci 1998;857:155–179.
Hungerford JE, Little CD. Developmental biology of the vascular smooth muscle cell: building a multilayered vessel wall. J Vasc Res 1999;36:2–27.
Bergwerff M, Verberne ME, DeRuiter MC, Poelmann RE, Gittenbergerde Groot AC. Neural crest cell contribution to the developing circulatory system: implications for vascular morphology? Circ Res 1998;82:221–231.
Etchevers HC, Couly GF, Le Douarin NM. Morphogenesis of the branchial vascular sector. Trends Cardiovasc Med 2002;12:299–304.
Vrancken Peeters MP, Gittenberger-de Groot AC, Mentink MM, Poelmann RE. Smooth muscle cells and fibroblasts of the coronary arteries derive from the epithelial-mesenchymal transformation of the epicardium. Anat Embryol (Berl) 1999;199:367-378.
D’Amor PA. Capillary growth: a two-cell system. Semin Cancer Biol 1997;3:49–56.
Gerhardt H, Wolburg H, Redies C. N-Cadherin mediates pericytic endothelial interaction during brain angiogenesis in the chicken. Dev Dyn 2000;218:472–479.
Uemura A, Ogawa M, Hirashima M, et al. Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells. J Clin Invest 2002;110:1619–1628.
Bianco P, Riminucci M. The bone marrow stroma in vivo: ontogeny, structure, cellular composition and changes in disease. In: Beresford JN, Owen M, eds. Marrow Stromal Cell Cultures. Cambridge University Press, Cambridge, UK, 1998, pp. 10–25.
Ascenzi A. Physiological relationship and pathological interferences between bone tissue and marrow. In: Bourne GH, ed. The Biochemistry and Physiology of Bone. Academic Press, New York, 1976, pp. 403–445.
Andreeva ER, Pugach IM, Gordon D, et al. Continuous subendothelial network formed by pericytelike cells in human vascular bed. Tissue Cell 1998;30:127–135.
Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 2001;19:180–192.
Ema M, Faloon P, Zhang WJ, et al. Combinatorial effects of Flk1 and Tal1 on vascular and hematopoietic development in the mouse. Genes Dev 2003;17:380–393.
Yamashita J, Itoh H, Hirashima M, et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 2000;408:92–96.
Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998;125:1591–1598.
Gerber HP, Vu TH, Ryan AM et al. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 1999;5:623–628.
Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430–436.
Klug MG, Soonpaa MH, Koh GY, Field LJ. Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J Clin Invest 1996;98:216–224.
Hescheler J, Fleischmann BK, Wartenberg M, et al. Establishment of ionic channels and signalling cascades in the embryonic stem cell-derived primitive endoderm and cardiovascular system. Cells Tissues Organs 1999;165:153–164.
Makino S, Fukuda K, Miyoshi S, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 1999;103:697–705.
Tomita S, Li R-K, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 1999;100:II–247.
Liechty KW, MacKenzie TC, Shaaban AF, et al. Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 2000;6:1282–1286.
Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler, D. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2003;105:93–96.
Beauchamp JR, Morgan JE, Pagel CN, Partridge TA. Dynamics of myoblast transplantation reveal a discrete minority of precursors with stem cell-like properties as the myogenic source. J Cell Biol 1999;144:1113–1122.
Smythe GM, Grounds MD. Exposure to tissue culture conditions can adversely affect myoblast behaviour in vivo in whole muscle grafts: implications for myoblast transfer therapy. Cell Transplant 2000;9:379–393.
Smythe GM, Hodgetts SI, Grounds MD. Problems and solutions in myoblast transfer therapy. J Cell Mol Med 2001;5:33–47.
Hodgetts SI, Beilharz MW, Scalzo T, Grounds MD. Why do cultured transplanted myoblasts die in vivo? DNA quantification shows enhanced survival of donor male myoblasts in host mice depleted of CD4+ and CD8+ or NK1.1+ cells. Cell Transplant 2000;9:489–502.
Mangi AA, Noiseux N, Kong D, et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 2003;9:1195–1201.
Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002;99:3838–3843.
Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic propertiesof differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003;31:890–896.
Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan E. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 2003;75:389–397.
Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004;363:1439–1441.
Arinzeh TL, Peter SJ, Archambault MP, et al. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. J Bone Joint Surg Am 2003;85-A(10):1927–1935.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Humana Press Inc., Totowa, NJ
About this chapter
Cite this chapter
Itescu, S., See, F., Martens, T. (2007). Mesenchymal Progenitor Cells for Vascular Network Formation and Cardiac Muscle Regeneration. In: Penn, M.S. (eds) Stem Cells And Myocardial Regeneration. Contemporary Cardiology. Humana Press. https://doi.org/10.1007/978-1-59745-272-4_5
Download citation
DOI: https://doi.org/10.1007/978-1-59745-272-4_5
Publisher Name: Humana Press
Print ISBN: 978-1-58829-664-1
Online ISBN: 978-1-59745-272-4
eBook Packages: MedicineMedicine (R0)