Research Article
No access
Published Online: 12 September 2013

Potential of Human Fetal Chorionic Stem Cells for the Treatment of Osteogenesis Imperfecta

Publication: Stem Cells and Development
Volume 23, Issue Number 3


Osteogenesis imperfecta (OI) is a genetic bone pathology with prenatal onset, characterized by brittle bones in response to abnormal collagen composition. There is presently no cure for OI. We previously showed that human first trimester fetal blood mesenchymal stem cells (MSCs) transplanted into a murine OI model (oim mice) improved the phenotype. However, the clinical use of fetal MSC is constrained by their limited number and low availability. In contrast, human fetal early chorionic stem cells (e-CSC) can be used without ethical restrictions and isolated in high numbers from the placenta during ongoing pregnancy. Here, we show that intraperitoneal injection of e-CSC in oim neonates reduced fractures, increased bone ductility and bone volume (BV), increased the numbers of hypertrophic chondrocytes, and upregulated endogenous genes involved in endochondral and intramembranous ossification. Exogenous cells preferentially homed to long bone epiphyses, expressed osteoblast genes, and produced collagen COL1A2. Together, our data suggest that exogenous cells decrease bone brittleness and BV by directly differentiating to osteoblasts and indirectly stimulating host chondrogenesis and osteogenesis. In conclusion, the placenta is a practical source of stem cells for the treatment of OI.

Get full access to this article

View all available purchase options and get full access to this article.


Dalgleish R. (1997). The human type I collagen mutation database. Nucleic Acids Res 25:181–187.
Cohen-Solal L, Zylberberg L, Sangalli A, Gomez Lira M and Mottes M. (1994). Substitution of an aspartic acid for glycine 700 in the alpha 2(I) chain of type I collagen in a recurrent lethal type II osteogenesis imperfecta dramatically affects the mineralization of bone. J Biol Chem 269:14751–14758.
Stoss H and Freisinger P. (1993). Collagen fibrils of osteoid in osteogenesis imperfecta: morphometrical analysis of the fibril diameter. Am J Med Genet 45:257
Van Dijk FS, Pals G, Van Rijn RR, Nikkels PG and Cobben JM. (2010). Classification of osteogenesis imperfecta revisited. Eur J Med Genet 53:1–5.
Letocha AD, Cintas HL, Troendle JF, Reynolds JC, Cann CE, et al. (2005). Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement. J Bone Miner Res 20:977–986.
Ward LM, Rauch F, Whyte MP, D'Astous J, Gates PE, et al. (2011). Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J Clin Endocrinol Metab 96:355–364.
Rauch F and Glorieux FH. (2004). Osteogenesis imperfecta. Lancet 363:1377–1385.
Horwitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA, et al. (2001). Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 97:1227–1231.
Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, et al. (2002). Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci USA 99:8932–8937.
Le Blanc K, Gotherstrom C, Ringden O, Hassan M, McMahon R, et al. (2005). Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation 79:1607–1614.
Pereira RF, O'Hara MD, Laptev AV, Halford KW, Pollard MD, et al. (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.
Panaroni C, Gioia R, Lupi A, Besio R, Goldstein SA, et al. (2009). In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta. Blood 114:459–468.
Wang X, Li F and Niyibizi C. (2006). Progenitors systemically transplanted into neonatal mice localize to areas of active bone formation in vivo: implications of cell therapy for skeletal diseases. Stem Cells 24:1869–1878.
Li F, Wang X and Niyibizi C. (2007). Distribution of single-cell expanded marrow derived progenitors in a developing mouse model of osteogenesis imperfecta following systemic transplantation. Stem Cells 25:3183–3193.
Guillot PV, Abass O, Bassett JH, Shefelbine SJ, Bou-Gharios G, et al. (2008). Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice. Blood 111:1717–1725.
Vanleene M, Saldanha Z, Cloyd KL, Jell G, Bou-Gharios G, et al. (2011). Transplantation of human fetal blood stem cells in the osteogenesis imperfecta mouse leads to improvement in multiscale tissue properties. Blood 117:1053–1060.
Portmann-Lanz CB, Schoeberlein A, Huber A, Sager R, Malek A, et al. (2006). Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration. Am J Obstet Gynecol 194:664–673.
Poloni A, Rosini V, Mondini E, Maurizi G, Mancini S, et al. (2008). Characterization and expansion of mesenchymal progenitor cells from first-trimester chorionic villi of human placenta. Cytotherapy 10:690–697.
Barlow S, Brooke G, Chatterjee K, Price G, Pelekanos R, et al. (2008). Comparison of human placenta- and bone marrow-derived multipotent mesenchymal stem cells. Stem Cells Dev 17:1095–1107.
Soncini M, Vertua E, Gibelli L, Zorzi F, Denegri M, et al. (2007). Isolation and characterization of mesenchymal cells from human fetal membranes. J Tissue Eng Regen Med 1:296–305.
Li CD, Zhang WY, Li HL, Jiang XX, Zhang Y, et al. (2005). Isolation and identification of a multilineage potential mesenchymal cell from human placenta. Placenta [Epub ahead of print];.
Yen BL, Huang HI, Chien CC, Jui HY, Ko BS, et al. (2005). Isolation of multipotent cells from human term placenta. Stem Cells 23:3–9.
Jones GN, Moschidou D, Puga-Iglesias TI, Kuleszewicz K, Vanleene M, et al. (2012). Ontological differences in first compared to third trimester human fetal placental chorionic stem cells. PLoS One 7:e43395
Guillot PV, Gotherstrom C, Chan J, Kurata H, Fisk NM. (2007). Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC. Stem Cells 25:646–654.
Bassett JH, Boyde A, Howell PG, Bassett RH, Galliford TM, et al. (2010). Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts. Proc Natl Acad Sci USA 107:7604–7609.
Chappard D, Palle S, Alexandre C, Vico L and Riffat G. (1987). Bone embedding in pure methyl methacrylate at low temperature preserves enzyme activities. Acta Histochem 81:183–190.
Yongchang Y and Wang Y. (2013). ATDC5: An excellent in vitro model cell line for skeletal development. J Cell Biochem 114:1223–1229.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317.
Adewumi O, Aflatoonian B, Ahrlund-Richter L, Amit M, Andrews PW, et al. (2007). Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol 25:803–816.
Skottman H, Mikkola M, Lundin K, Olsson C, Stromberg AM, et al. (2005). Gene expression signatures of seven individual human embryonic stem cell lines. Stem Cells 23:1343–1356.
Gotherstrom C, Ringden O, Tammik C, Zetterberg E, Westgren M, et al. (2004). Immunologic properties of human fetal mesenchymal stem cells. Am J Obstet Gynecol 190:239–245.
McKee MD and Nanci A. (1996). Osteopontin: an interfacial extracellular matrix protein in mineralized tissues. Connect Tissue Res 35:197–205.
Lian JB, Stein GS, Stewart C, Puchacz E, Mackowiak S, et al. (1989). Osteocalcin: characterization and regulated expression of the rat gene. Connect Tissue Res 21:61–68; discussion 69.
Ryoo HM, Hoffmann HM, Beumer T, Frenkel B, Towler DA, et al. (1997). Stage-specific expression of Dlx-5 during osteoblast differentiation: involvement in regulation of osteocalcin gene expression. Mol Endocrinol 11:1681–1694.
Chipman SD, Sweet HO, McBride DJ Jr., Davisson MT, Marks SC Jr., et al. (1993). Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta. Proc Natl Acad Sci USA 90:1701–1705.
James CG, Stanton LA, Agoston H, Ulici V, Underhill TM, et al. (2010). Genome-wide analyses of gene expression during mouse endochondral ossification. PLoS One 5:e8693
Haleem-Smith H, Calderon R, Song Y, Tuan RS and Chen FH. (2012). Cartilage oligomeric matrix protein enhances matrix assembly during chondrogenesis of human mesenchymal stem cells. J Cell Biochem 113:1245–1252.
Bi W, Deng JM, Zhang Z, Behringer RR and de Crombrugghe B. (1999). Sox9 is required for cartilage formation. Nat Genet 22:85–89.
Bell DM, Leung KK, Wheatley SC, Ng LJ, Zhou S, et al. (1997). SOX9 directly regulates the type-II collagen gene. Nat Genet 16:174–178.
Lefebvre V, Huang W, Harley VR, Goodfellow PN and de Crombrugghe B. (1997). SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene. Mol Cell Biol 17:2336–2346.
Tsuji Y, Shimada Y, Takeshita T, Kajimura N, Nomura S, et al. (2000). Cryptic dimer interface and domain organization of the extracellular region of metabotropic glutamate receptor subtype 1. J Biol Chem 275:28144–28151.
Muir H. (1995). The chondrocyte, architect of cartilage. Biomechanics, structure, function and molecular biology of cartilage matrix macromolecules. Bioessays 17:1039–1048.
Amano K, Hata K, Sugita A, Takigawa Y, Ono K, et al. (2009). Sox9 family members negatively regulate maturation and calcification of chondrocytes through up-regulation of parathyroid hormone-related protein. Mol Biol Cell 20:4541–4551.
Huang W, Chung UI, Kronenberg HM and de Crombrugghe B. (2001). The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones. Proc Natl Acad Sci USA 98:160–165.
Huang W, Zhou X, Lefebvre B and de Crombrugghe V. (2000). Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer. Mol Cell Biol 20:4149–4158.
Ferguson CM, Schwarz EM, Reynolds PR, Puzas JE, Rosier RN, et al. (2000). Smad2 and 3 mediate transforming growth factor-beta1-induced inhibition of chondrocyte maturation. Endocrinology 141:4728–4735.
Arias JL, Nakamura O, Fernandez MS, Wu JJ, Knigge P, et al. (1997). Role of type X collagen on experimental mineralization of eggshell membranes. Connect Tissue Res 36:21–33.
Martin A, Liu S, David V, Li H, Karydis A, et al. (2011). Bone proteins PHEX and DMP1 regulate fibroblastic growth factor Fgf23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB J 25:2551–2562.
Lorenz-Depiereux B, Bastepe M, Benet-Pages A, Amyere M, Wagenstaller J, et al. (2006). DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nat Genet 38:1248–1250.
Wang X, Harimoto K, Xie S, Cheng H, Liu J, et al. (2010). Matrix protein biglycan induces osteoblast differentiation through extracellular signal-regulated kinase and Smad pathways. Biol Pharm Bull 33:1891–1897.
Christiansen HE, Schwarze U, Pyott SM, Al Swaid A, Al Balwi M, et al. (2010). Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet 86:389–398.
Stacey A, Bateman J, Choi T, Mascara T, Cole W, et al. (1988). Perinatal lethal osteogenesis imperfecta in transgenic mice bearing an engineered mutant pro-alpha 1(I) collagen gene. Nature 332:131–136.
Ducy P, Zhang R, Geoffroy V, Ridall AL and Karsenty G. (1997). Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89:747–754.
Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, et al. (1997). Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–764.
Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, et al. (1997). Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89:765–771.
Karsenty G and Wagner EF. (2002). Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2:389–406.
Kurata H, Guillot PV, Chan J and Fisk NM. (2007). Osterix induces osteogenic gene expression but not differentiation in primary human fetal mesenchymal stem cells. Tissue Eng 13:1513–1523.
Giustina A, Mazziotti G and Canalis E. (2008). Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 29:535–559.
Mochizuki H, Hakeda Y, Wakatsuki N, Usui N, Akashi S, et al. (1992). Insulin-like growth factor-I supports formation and activation of osteoclasts. Endocrinology 131:1075–1080.
Niu T and Rosen CJ. (2005). The insulin-like growth factor-I gene and osteoporosis: a critical appraisal. Gene 361:38–56.
Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, et al. (2002). Circulating levels of IGF-1 directly regulate bone growth and density. J Clin Invest 110:771–781.
Jones GN, Moschidou D, Lay K, Abdulrazzak H, Vanleene M, et al. (2012). Upregulating CXCR4 in human fetal mesenchymal stem cells enhances engraftment and bone mechanics in a mouse model of osteogenesis imperfecta. Stem Cells Transl Med 1:70–78.
Granero-Molto F, Weis JA, Miga MI, Landis B, Myers TJ, et al. (2009). Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells 27:1887–1898.
Li H, Jiang X, Delaney J, Franceschetti T, Bilic-Curcic I, et al. (2010). Immature osteoblast lineage cells increase osteoclastogenesis in osteogenesis imperfecta murine. Am J Pathol 176:2405–2413.
Kalajzic I, Terzic J, Rumboldt Z, Mack K, Naprta A, et al. (2002). Osteoblastic response to the defective matrix in the osteogenesis imperfecta murine (oim) mouse. Endocrinology 143:1594–1601.
Zhou Y, Fan W, Prasadam I, Crawford R and Xiao Y. (2012). Implantation of osteogenic differentiated donor mesenchymal stem cells causes recruitment of host cells. J Tissue Eng Regen Med.
Li X, Ling W, Pennisi A, Wang Y, Khan S, et al. (2011). Human placenta-derived adherent cells prevent bone loss, stimulate bone formation, and suppress growth of multiple myeloma in bone. Stem Cells 29:263–273.
Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, et al. (2003). Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol 162:833–842.
Otsuru S, Gordon PL, Shimono K, Jethva R, Marino R, et al. (2012). Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms. Blood 120:1933–1941.
Zebaze RM, Jones AC, Pandy MG, Knackstedt MA and Seeman E. (2011). Differences in the degree of bone tissue mineralization account for little of the differences in tissue elastic properties. Bone 48:1246–1251.
Gupta HS, Schratter S, Tesch W, Roschger P, Berzlanovich A, et al. (2005). Two different correlations between nanoindentation modulus and mineral content in the bone-cartilage interface. J Struct Biol 149:138–148.
Vanleene M, Porter A, Guillot PV, Boyde A, Oyen M, et al. (2012). Ultra-structural defects cause low bone matrix stiffness despite high mineralization in osteogenesis imperfecta mice. Bone 50:1317–1323.
Frayssinet P, Jouve JL and Viehweger. E (2004). Cartilage cells. In: Biomechanics and Biomaterials in Orthopaedics. Thorngren KG, Poitout DG, Kotz R, eds. Springer, London, pp 219.

Information & Authors


Published In

cover image Stem Cells and Development
Stem Cells and Development
Volume 23Issue Number 3February 1, 2014
Pages: 262 - 276
PubMed: 24028330


Published in print: February 1, 2014
Published ahead of print: 16 October 2013
Published online: 12 September 2013
Accepted: 12 September 2013
Received: 11 March 2013


Request permissions for this article.




    Gemma N. Jones
    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
    Dafni Moschidou*
    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
    Hassan Abdulrazzak
    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
    Bhalraj Singh Kalirai
    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
    Maximilien Vanleene
    Department of Bioengineering, Imperial College London, London, United Kingdom.
    Suchaya Osatis
    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
    Sandra J. Shefelbine
    Department of Bioengineering, Imperial College London, London, United Kingdom.
    Nicole J. Horwood
    Kennedy Institute of Rheumatology, Imperial College London, London, United Kingdom.
    Massimo Marenzana
    Department of Bioengineering, Imperial College London, London, United Kingdom.
    Paolo De Coppi
    Surgery Unit, UCL Institute of Child Health, London, United Kingdom.
    J.H. Duncan Bassett
    Molecular Endocrinology Group, Department of Medicine, Imperial College London, London, United Kingdom.
    Graham R. Williams
    Molecular Endocrinology Group, Department of Medicine, Imperial College London, London, United Kingdom.
    Nicholas M. Fisk
    UQ Centre for Clinical Research, University of Queensland, Brisbane, Australia.
    Pascale V. Guillot
    Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.


    Address correspondence to:Dr. Pascale V. GuillotInstitute of Reproductive and Developmental BiologyImperial College LondonDu Cane RoadLondon W12 0NNUnited Kingdom
    E-mail: [email protected]

    Author Disclosure Statement

    The authors declare no competing financial interests exist.

    Metrics & Citations



    Export citation

    Select the format you want to export the citations of this publication.

    View Options

    Get Access

    Access content

    To read the fulltext, please use one of the options below to sign in or purchase access.

    Society Access

    If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

    Restore your content access

    Enter your email address to restore your content access:

    Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

    View options


    View PDF/ePub

    Full Text

    View Full Text







    Copy the content Link

    Share on social media

    Back to Top