Skip to main content

Advertisement

Log in

Reproductive Stem Cell Differentiation: Extracellular Matrix, Tissue Microenvironment, and Growth Factors Direct the Mesenchymal Stem Cell Lineage Commitment

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The mesenchymal stem cells (MSCs) have awakened interest in regenerative medicine due to its high capability to proliferate and differentiate in multiple specialized lineages under defined conditions. The reproductive system is considered a valuable source of MSCs, which needs further investigations. Many factors have been reported as critical for these cell lineage specification and determination. In this review, we discuss the main effects of extracellular matrix or tissue environment and growth factors in the cell lineage commitment, including the reproductive stem cells. The MSCs responses to culture medium stimuli or to soluble factors probably occur through several intracellular activation pathways. However, the molecular mechanisms in which the cells respond to these mechanical or chemical perturbations remain elusive. Recent findings suggest a synergic effect of microenvironment and soluble cell culture factors affecting cell differentiation. For future applications in cell therapy, protocols of reproductive MSCs differentiation must be established.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. World Health Organization. Make every mother and child count. World health report. 2005; 1211 Geneva 27, Switzerland.

  2. Masuda H, Matsuzaki Y, Hiratsu E, et al. Stem cell-like properties of the endometrial side population: implication in endometrial regeneration. PloS one. 2010;5(4):e10387.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Taylor HS, Osteen KG, Bruner-Tran KL, et al. Novel therapies targeting endometriosis. Reprod Sci. 2011;18(9):814–823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Du H, Taylor SH. Stem cells and reproduction. Curr Opin Obstet Gynecol. 2010;22(3):235–241.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hayashi Y, Saitou M, Yamanaka S. Germline development from human pluripotent stem cells toward disease modeling of infertility. Fertil Steril. 2012;97(6):1250–1259.

    Article  PubMed  Google Scholar 

  6. Hutt KJ, Albertini DF. Clinical applications and limitations of current ovarian stem cell research: A review. J Exp Clin Assist Reprod. 2006;3(6). doi: 10.1186/1743-1050-3-6.

  7. Bukovsky A, Caudle MR, Carson RJ, et al. Immune physiology in tissue regeneration and aging, tumor growth and regenerative medicine. Aging. 2009;1(2):157–181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292(1):81–85.

    Article  CAS  PubMed  Google Scholar 

  9. Wolff EF, Wolff AB, Hongling DU, Taylor HS. Demonstration of multipotent stem cells in the adult human endometrium by in vitro chondrogenesis. Reprod Sci. 2007;14(6):524–533.

    Article  CAS  PubMed  Google Scholar 

  10. Du H, Taylor SH. Stem cells and female reproduction. Reprod Sci. 2009;16(2):126–139.

    Article  PubMed  Google Scholar 

  11. Martin DR, Cox NR, Hathcock TL, Niemeyer GP, Baker HJ. Isolation and characterization of multipotential mesenchymal stem cells from feline bone marrow. Exp Hematol. 2002;30(8): 879–886.

    Article  CAS  PubMed  Google Scholar 

  12. Herzog EL, Chai L, Krause DS. Plasticity of marrow-derived stem cells. Blood. 2003;102(10):3483–3493.

    Article  CAS  PubMed  Google Scholar 

  13. Mohr S, Portmann-lanz CB, Schoeberlein A, Sager R, Surbek DV. Generation of an osteogenic graft from human placenta and placenta-derived mesenchymal stem cells. Reprod Sci. 2010; 17(11):1006–1015.

    Article  CAS  PubMed  Google Scholar 

  14. Abreu SC, Antunes MA, Pelosi P, Morales MM, Rocco PRM. Mechanisms of cellular therapy in respiratory diseases. Intens Care Med. 2011;37(9):1421–1431.

    Article  Google Scholar 

  15. Kuijk EW, Lopes SMCS, Geijsen N, Macklon N, Roelen BAJ. The different shades of mammalian pluripotent stem cells. Hum Reprod Update. 2011;17(2):254–271.

    Article  CAS  PubMed  Google Scholar 

  16. Lin GL, Hankenson KD. Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem. 2011;112(12):3491–3501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Semb H. Human embryonic stem cells: origin, properties and applications. APMIS. 2005;113(11–12):743–750.

    Article  PubMed  Google Scholar 

  18. Gattegno-Ho D, Argyle SA, Argyle DJ. Stem cells and veterinary medicine: tools to understand diseases and enable tissue regeneration and drug discovery. Vet J (London, England: 1997). 2012; 191(1):19–27.

    Article  Google Scholar 

  19. Hayashi Y, Tsuji S, Tsujii M, et al. Topical transplantation of mesenchymal stem cells accelerates gastric ulcer healing in rats. Am J Physiol Gastrointest Liver Physiol. 2008;294(3): G778–G786.

    Article  CAS  PubMed  Google Scholar 

  20. Bianchi G, Muraglia A, Daga A, Corte G, Cancedda R, Quarto R. Microenvironment and stem properties of bone marrow-derived mesenchymal cells. Wound Repair Regen. 2001;9(6):460–466.

    Article  CAS  PubMed  Google Scholar 

  21. Meirelles LS, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119(Pt 11):2204–2213.

    Article  CAS  Google Scholar 

  22. Gandolfi F, Brevini TAL, Cillo F, Antonini S. Cellular and molecular mechanisms regulating oocyte quality and the relevance for farm animal reproductive efficiency. Rev Sci Tech. 2005;24(1):413–423.

    Article  CAS  PubMed  Google Scholar 

  23. Hu FF, Jing XU, Cui YG, et al. Isolation and characterization of side population cells in the postpartum murine endometrium. Reprod Sci. 2010;17(7):629–642.

    Article  PubMed  CAS  Google Scholar 

  24. Deans RJ, Moseley AB. Mesenchymal stem cells: Biology and potential clinical uses. Exp Hematol. 2000;28(8):875–884.

    Article  CAS  PubMed  Google Scholar 

  25. Vããnãnen HK. Mesenchymal stem cells. Ann Med. 2005;37(7): 469–479.

    Article  PubMed  CAS  Google Scholar 

  26. Bittencourt RAC, Pereira HR, Felisbino SL, Murador P, Oliveira APE, Deffune E. Isolation of bone marrow mesenchymal stem cells. Acta Ortop Bras. 2011;14(1):22–24.

    Article  Google Scholar 

  27. Kanitkar M, Tailor HD, Khan WS. The use of growth factors and mesenchymal stem cells in orthopaedics. Open Orthop J. 2011; 5(2):271–275.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bae KS, Park JB, Kim HS, Kim DS, Park DJ, Kang SJ. Neuronlike Differentiation of bone marrow-derived mesenchymal stem cells. Yonsei Med J. 2011;52(3):401–412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Orlic D, Kajstura J, Chimenti S, et al. Mobilized bone marrow cells repair the infracted heart, improving function and survival. Proc Natl Acad Sci U S A. 2001;98(18):10344–10349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest. 2002;109(3):337–346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hayashi Y, Tsuji S, Tsujii M, et al. Topical Implantation of Mesenchymal Stem Cells Has Beneficial Effects on Healing of Experimental Colitis in Rats. J Pharmacol Exp Ther. 2008; 326(2):523–531.

    Article  CAS  PubMed  Google Scholar 

  32. Lange C, Bassler P, Lioznov MV, et al. Liver-specific gene expression in mesenchymal stem cells is induced by liver cells. World J Gastroenterol. 2005;11(29):4497–4504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sato Y, Araki H, Kato J, et al. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 2005;106(2):756–763.

    Article  CAS  PubMed  Google Scholar 

  34. Morelli SS, Yi P, Goldsmith LT. Endometrial stem cells and reproduction [published online January 12, 2012]. Obstet Gynecol Int. 2012.

  35. Sanchez-Ramos J, Song S, Cardozo-Pelaez, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol. 2000;164(2):247–256.

    Article  CAS  PubMed  Google Scholar 

  36. Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418(6893):41–49.

    Article  CAS  PubMed  Google Scholar 

  37. Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells. 2001;19(3):180–192.

    Article  CAS  PubMed  Google Scholar 

  38. Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. 2000;61(4):364–370.

    Article  CAS  PubMed  Google Scholar 

  39. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306(5701): 1568–1571.

    Article  CAS  PubMed  Google Scholar 

  40. Barry FP, Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell B. 2004; 36(4):568–584.

    Article  CAS  Google Scholar 

  41. McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell. 2004;6(4):483–495.

    Article  CAS  PubMed  Google Scholar 

  42. Grassel S, Ahmed N. Influence of cellular microenvironment and paracrine signals on chondrogenic differentiation. Front Biosci. 2007;12:4946–4956. doi: 10.2741/2440.

    Article  CAS  PubMed  Google Scholar 

  43. Bianco P, Robey PG. Stem cells in tissue engineering. Nature. 2001;414(6859):118–121.

    Article  CAS  PubMed  Google Scholar 

  44. Schneider PRA, Buhrmann C, Mobasheri A, Matis U, Shakibaei M. Three-dimensional high-density co-culture with primary tenocytes induces tenogenic differentiation in mesenchymal stem cells. J Orthopaed Res. 2011;29(9):1351–1360.

    Article  CAS  Google Scholar 

  45. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126(4):677–689.

    Article  CAS  PubMed  Google Scholar 

  46. Even-Ram S, Artym V, Yamada KM. Matrix control of stem cell fate. Cell. 2006;126(4):645–647.

    Article  CAS  PubMed  Google Scholar 

  47. Hwang NS, Varghese S, Li H, Elisseeff J. Regulation of osteogenic and chondrogenic differentiation of mesenchymal stem cells in PEG-ECM hydrogels. Cell Tissue Res. 2011;344(3): 499–509.

    Article  CAS  PubMed  Google Scholar 

  48. Ravindran S, Gao Q, Kotecha M, Magin RL, Karol S, Bedran-Russo A, George A. Biomimetic ECM Incorporated Scaffold Induces Osteogenic Gene Expression in Human Marrow Stromal Cells. Tissue Eng. Part A. 2012;18(3–4):295–309.doi: 10.1089/ten.TEA.0136, 1–40.

    Article  CAS  PubMed  Google Scholar 

  49. Huang S, Ingber DE. Cell tension, matrix mechanics, and câncer development. Cancer cell. Previews. 2005;8(3):175–176.

    Article  CAS  Google Scholar 

  50. Bershadsky AD, Balaban NQ, Geiger B. Adhesion-dependent cell mechanosensitivity. Annu Rev Cell Dev Biol. 2003;19:677–695. doi: 10.1146/annurev.cellbio.19.111301.153011.

    Article  CAS  PubMed  Google Scholar 

  51. Discher DE, Janmey P, Wang Y. Tissue cells feel and respond to the stiffness of their substrate. Science. 2005;310(5751): 1139–1143.

    Article  CAS  PubMed  Google Scholar 

  52. Sawada Y, Tamada M, Thaler BJD, et al. Force sensing by mechanical extension of the src family kinase substrate p130Cas. Cell. 2006;127(5):1015–1026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Griffith LG, Swartz MA. Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol. 2006;7(3):211–224.

    Article  CAS  PubMed  Google Scholar 

  54. Giannone G, Sheetz MP. Substrate rigidity and force define form through tyrosine phosphatase and kinase pathways. Trends Cell Biol. 2006;16(4):213–223.

    Article  CAS  PubMed  Google Scholar 

  55. Ingber DE. Cellular mechanotransduction: putting all the pieces together again. FASEB J. 2006;20(7):811–827.

    Article  CAS  PubMed  Google Scholar 

  56. Davis HE, Case EM, Miller SL, Genetos DC, Leach JK. Osteogenic response to BMP-2 of hMSCs grown on apatite-coated scaffolds. Biotechnol Bioeng. 2011;108(11):2727–2735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vogel V, Sheetz M. Local force and geometry sensing regulate cell functions. Nat Rev Mol Cell Biol. 2006;7(4):265–275.

    Article  CAS  PubMed  Google Scholar 

  58. Raghavan S, Shen CJ, Desai RA, Sniadecki NJ, Nelson CM, Chen CS. Decoupling diffusional from dimensional control of signaling in 3D culture reveals a role for myosin in tubulogenesis. J Cell Sci. 2010;123(17):2877–2883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Curran JM, Chen R, Hunt JA. The guidance of human mesenchymal stem cell differentiation in vitro by controlled modifications to the cell substrate. Biomaterials. 2006;27(27):4783–4793.

    Article  CAS  PubMed  Google Scholar 

  60. Jurgens WJFM, Lu Z, Zandieh-Doulabi B, Kuik DJ, Ritt MJPF, Helder MN. Hyperosmolarity and hypoxia induce chondrogenesis of adipose-derived stem cells in a collagen type 2 hydrogel. J Tissue Eng Regen Med. 2011;6(7):570–578.

    Article  PubMed  CAS  Google Scholar 

  61. Takahashi K, Tanabe K, Ohnuki M, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–872.

    Article  CAS  PubMed  Google Scholar 

  62. Schmitt B, Ringe J, Haupl T, et al. BMP2 initiates chondrogenic lineage development of adult human mesenchymal stem cells in high-density culture. Differentiation. 2003;71:567–577.

    Article  CAS  PubMed  Google Scholar 

  63. Davidson D, Blanc A, Filion D, et al. Fibroblast growth factor (FGF) 18 signals through FGF receptor 3 to promote chondrogenesis. J Biol Chem. 2005;280(21):20509–20515.

    Article  CAS  PubMed  Google Scholar 

  64. Hwang NS, Varghese S, Puleo C, Zhang Z, Elisseeff J. Morphogenetic signals from chondrocytes promote chondrogenic and osteogenic differentiation of mesenchymal stem cells. J Cell Physiol. 2007;212(2):281–284.

    Article  CAS  PubMed  Google Scholar 

  65. Hanada K, Dennis JE, Caplan AJ. Stimulatory effects of basic fibroblast growth factor and bone morphogenetic protein-2 on osteogenic differentiation of rat bone marrow derived mesenchymal stem cells. J Bone Miner Res. 1997;12(10):1606–1614.

    Article  CAS  PubMed  Google Scholar 

  66. Zhou S, Turgeman G, Harris SE, et al. Estrogens activate bone morphogenetic protein-2 gene transcription in mouse mesenchymal stem cells. Mol Endocrinol. 2003;17(1):56–66.

    Article  CAS  PubMed  Google Scholar 

  67. Fierro FA, Kalomoiris S, Sondergaard CS, Nolta JA. Effects on proliferation and differentiation of multipotent bone marrow stromal cells engineered to express growth factors for combined cell and gene therapy. Stem Cells. 2011;29(11):1727–1737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gorter DJJ, van Dinther M, Korchynskyi O, ten Dijke P. Biphasic effects of transforming growth factor b on bone morphogenetic protein–induced osteoblast differentiation. J Bone Miner Res. 2011;26(6):1178–1187.

    Article  PubMed  CAS  Google Scholar 

  69. Janderova L, McNeil M, Murrell AN, Mynatt RL, Smith SR. Human mesenchymal stem cells as an in vitro model for human adipogenesis. Obes Res. 2003;11(1):65–74.

    Article  CAS  PubMed  Google Scholar 

  70. Neubauer M, Fischbach C, Bauer-Kreisel P, et al. Basic fibroblast growth factor enhances PPARγ ligand-induced adipogenesis of mesenchymal stem cells. FEBS Lett. 2004;577(1–2):277–283.

    Article  CAS  PubMed  Google Scholar 

  71. Kakudo N, Shimotsuma A, Kusumoto K. Fibroblast growth factor-2 stimulates adipogenic differentiation of human adipose-derived stem cells. Biochem Bioph Res Co. 2011; 359(2):239–244.

    Article  CAS  Google Scholar 

  72. van den Bos C, Mosca J, Winkles J, Kerrigan L, Burgess WH, Marshak DR. Human mesenchymal stem cells respond to fibroblast growth factors. Human Cell. 1997;10(1):45–50.

    PubMed  Google Scholar 

  73. MacDonald KK, Cheung CY, Anseth KS. Cellular delivery of TGFβ1 promotes osteoinductive signalling for bone regeneration. J Tissue Eng Regen Med. 2007;1(4):314–317.

    Article  CAS  PubMed  Google Scholar 

  74. Del Carlo RJ, Monteiro BS, Argôlo Neto NM. Células-tronco e fatores de crescimento na reparação tecidual. Ciênc vet Tróp. 2008;11(1):167–169.

    Google Scholar 

  75. Kuznetsov SA, Friedenstein AJ, Robey PG. Factors required for bone marrow stromal fibroblast colony formation in vitro. Brit J Haematol. 1997;97(3):561–570.

    Article  CAS  Google Scholar 

  76. Schwab KE, Chan RW, Gargett CE. Putative stem cell activity of human endometrial epithelial and stromal cells during the menstrual cycle. Fertil Steril. 2005;84(suppl 2):1124–1130.

    Article  CAS  PubMed  Google Scholar 

  77. Chan RW, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod. 2004; 70(6):1738–1750.

    Article  CAS  PubMed  Google Scholar 

  78. Kulak JJ, Ferriani AR, Komm BS, Taylor HS. Tissue selective estrogen complexes (TSECs) differentially modulate markers of proliferation and differentiation in endometrial cells. Reprod Sci. 2013;20(2):129–137.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Cuevas P, Burgos J, Baird A. Basic fibroblast growth factor (FGF) promotes cartilage repair in vivo. Biochem Bioph Res Co. 1988; 156(2):611–618.

    Article  CAS  Google Scholar 

  80. Mackay AM, Beck SC, Murphy JM, Barry FP, Chichester CO, Pittenger MF. Chondrogenic differentiation of cultured human mesenchymal stem cells from marrow. Tissue Eng. 1998;4(4): 415–428.

    Article  CAS  PubMed  Google Scholar 

  81. Chen D, Ji X, Harris MA, et al. Differential roles for bone marrow morphogenetic protein (BMP) receptor type IB and IA in differentiation and specification of mesenchymal precursor cells to osteoblast and adipocyte lineages. J Cell Biol. 1998;142(1): 295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yonezawa T, Lee JW, Hibino A. Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling. Biochem Bioph Res Co. 2011;409(2):260–265.

    Article  CAS  Google Scholar 

  83. Grgurevic L, Macek B, Mercep M, et al. Bone morphogenetic protein (BMP)1-3 enhances bone repair. Biochem Bioph Res Co. 2011;408(1):25–31.

    Article  CAS  Google Scholar 

  84. Wen Q, Zhou L, Zhou C, Zhou M, Luo W, Ma L. Change in hepatocyte growth factor concentration promote mesenchymal stem cell-mediated osteogenic regeneration. J Cell Mol Med. 2012; 16(6):1260–1273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang Y, Zhang D, Ashraf M, et al. Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction. Am J Physiol-Heart C. 2010;298(1):275–286.

    Article  CAS  Google Scholar 

  86. Delcroix GJR, Curtis KM, Schiller PC, Montero-Menei CN. EGF and bFGF pre-treatment enhances neural specification and the response to neuronal commitment of MIAMI cells. Differentiation. 2010;80(4–5):213–227.

    Article  CAS  PubMed  Google Scholar 

  87. Pulavendran S, Rose C, Mandal AB. Hepatocyte growth factor incorporated chitosan nanoparticles augment the differentiation of stem cell into hepatocytes for the recovery of liver cirrhosis in mice. J Nanobiotechnology. 2011;9(15):1–11.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Carlos E. Ambrósio PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vidane, A.S., Zomer, H.D., Oliveira, B.M.M. et al. Reproductive Stem Cell Differentiation: Extracellular Matrix, Tissue Microenvironment, and Growth Factors Direct the Mesenchymal Stem Cell Lineage Commitment. Reprod. Sci. 20, 1137–1143 (2013). https://doi.org/10.1177/1933719113477484

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719113477484

Keywords

Navigation