Biochemistry (Moscow)

, Volume 84, Issue 3, pp 232–240 | Cite as

Extracellular Matrix in the Regulation of Stem Cell Differentiation

  • E. S. Novoseletskaya
  • O. A. Grigorieva
  • A. Yu. EfimenkoEmail author
  • N. I. Kalinina


Extracellular matrix (ECM) proteins fill the space between cells in multicellular organisms, contributing to the structure of organs and tissues. The mechanical properties of ECM are well studied. At present, the role of individual ECM components and the three-dimensional tissue-specific matrices in the regulation of cell functional activity, proliferation, migration, acquisition of a specialized phenotype and its maintenance is intensively studied. In this review, we described main ECM structural proteins, enzymes, and extracellular vesicles and present the data on the participation of ECM components in the regulation of stem cell differentiation and self-maintenance, as well as approaches to the modeling of stem cells microenvironment using decellularized ECM.


extracellular matrix stem cells differentiation stem cell niche extracellular vesicles decellularization 



(decellularized) extracellular matrix


matrix metalloproteinase


mesenchymal stromal cell


neurogenin 3


pancreatic and duodenal homeobox 1


transcriptional coactivator with PDZ-binding motif


transforming growth factor beta


Yes-associated protein


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rozario, T., and DeSimone, D. W. (2010) The extracellular matrix in development and morphogenesis: a dynamic view, Dev. Biol., 341, 126–140.CrossRefGoogle Scholar
  2. 2.
    Chen, F. M., and Liu, X. (2016) Advancing biomaterials of human origin for tissue engineering, Prog. Polym. Sci., 53, 86–168.CrossRefGoogle Scholar
  3. 3.
    Yi, S., Ding, F., Gong, L., and Gu, X. (2017) Extracellular matrix scaffolds for tissue engineering and regenerative medicine, Curr. Stem Cell Res. Ther., 12, 233–246.CrossRefGoogle Scholar
  4. 4.
    Egeblad, M., Rasch, M. G., and Weaver, V. M. (2010) Dynamic interplay between the collagen scaffold and tumor evolution, Curr. Opin. Cell Biol., 22, 697–706.CrossRefGoogle Scholar
  5. 5.
    Yurchenco, P. D. (2011) Basement membranes: cell scaf–foldings and signaling platforms, Cold Spring Harb. Perspect Biol., 3, a004911.Google Scholar
  6. 6.
    Naba, A., Clauser, K. R., Ding, H., Whittaker, C. A., Carr, S. A., and Hynes, R. O. (2016) The extracellular matrix: tools and insights for the “omics” era, Matrix Biol., 49, 10–24.CrossRefGoogle Scholar
  7. 7.
    Gattazzo, F., Urciuolo, A., and Bonaldo, P. (2014) Extracellular matrix: a dynamic microenvironment for stem cell niche, Biochim. Biophys. Acta, 1840, 2506–2519.CrossRefGoogle Scholar
  8. 8.
    Ragelle, H., Naba, A., Larson, B. L., Zhou, F., Prijic, M., Whittaker, C. A., Rosarioa, A. D., Langer, R., Hynes, R. O., and Anderson, D. G. (2017) Comprehensive proteom–ic characterization of stem cell–derived extracellular matri–ces, Biomaterials, 128, 147–159.CrossRefGoogle Scholar
  9. 9.
    Anderson, H. C. (1967) Electron microscopic studies of induced cartilage development and calcification, J. Cell Biol., 35, 81–101.CrossRefGoogle Scholar
  10. 10.
    Bonucci, E. (1967) Fine structure of early cartilage calcifi–cation, J. Ultrastruct. Res., 20, 33–50.CrossRefGoogle Scholar
  11. 11.
    Yanez–Mo, M., Siljander, P. R. M., Andreu, Z., Bedina Zavec, A., Borras, F. E., Buzas, E. I., Buzas, K., Casal, E., Cappello, F., Carvalho, J., Colas, E., Cordeiro–da Silva, A., Fais, S., Falcon–Perez, J. M., Ghobrial, I. M., Giebel, B., Gimona, M., Graner, M., Gursel, I., Gursel, M., Heegaard, N. H. H., Hendrix, A., Kierulf, P., Kokubun, K., Kosanovic, M., Kralj–Iglic, V., Kramer–Albers, E.–M., Laitinen, S., Lasser, C., Lener, T., Ligeti, E., Line, A., Lipps, G., Llorente, A., Lotvall, J., Mancek–Keber, M., Marcilla, A., Mittelbrunn, M., Nazarenko, I., Nolte–‘t Hoen, E. N. M., Nyman, T. A., O’Driscoll, L., Olivan, M., Oliveira, C., Pallinger, E., del Portillo, H. A., Reventos, J., Rigau, M., Rohde, E., Sammar, M., Sanchez–Madrid, F., Santarem, N., Schallmoser, K., Ostenfeld, M. S., Stoorvogel, W., Stukelj, R., Van der Grein, S. G., Vasconcelos, M. H., Wauben, M. H. M., and Colas, E. (2015) Biological properties of extracellular vesicles and their physiological functions, J. Extracell. Vesicles, 4, 27066.CrossRefGoogle Scholar
  12. 12.
    Kapustin, A., Davies, J. D., Reynolds, J. L., McNair, R., Jones, G. T., Sidibe, A., Schurgers, L. J., Skepper, J. N., Proudfoot, D., Mayr, M., and Shanahan, C. M. (2011) Calcium regulates key components of vascular smooth muscle cell–derived matrix vesicles to enhance mineraliza–tion, Circ. Res., 109, e1–e12.Google Scholar
  13. 13.
    Wang, X., Omar, O., Vazirisani, F., Thomsen, P., and Ekstrom, K. (2018) Mesenchymal stem cell–derived exo–somes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differ–entiation, PLoS One, 13, e0193059.Google Scholar
  14. 14.
    Nawaz, M., Shah, N., Zanetti, B., Maugeri, M., Silvestre, R., Fatima, F., Neder, L., and Valadi, H. (2018) Extracellular vesicles and matrix remodeling enzymes: the emerging roles in extracellular matrix remodeling, progres–sion of diseases and tissue repair, Cells, 7, E167.Google Scholar
  15. 15.
    Schofield, R. (1978) The relationship between the spleen colony–forming cell and the haemopoietic stem cell, Blood Cells, 4, 7–25.Google Scholar
  16. 16.
    Mashinchian, O., Pisconti, A., Le Moal, E., and Bentzinger, C. F. (2018) The muscle stem cell niche in health and disease, Curr. Top. Dev. Biol., 126, 23–65.CrossRefGoogle Scholar
  17. 17.
    Spit, M., Koo, B. K., and Maurice, M. M. (2018) Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer, Open Biol., 8, 180120.CrossRefGoogle Scholar
  18. 18.
    Guo, P., Sun, H., Zhang, Y., Tighe, S., Chen, S., Su, C. W., Liu, Y., Zhao, H., Hu, M., and Zhu, Y. (2018) Limbal niche cells are a potent resource of adult mesenchymal pro–genitors, J. Cell Mol. Med., 22, 3315–3322.CrossRefGoogle Scholar
  19. 19.
    Matarredona, E. R., Talaveron, R., and Pastor, A. M. (2018) Interactions between neural progenitor cells and microglia in the subventricular zone: physiological implica–tions in the neurogenic niche and after implantation in the injured brain, Front. Cell Neurosci., 12, 268.CrossRefGoogle Scholar
  20. 20.
    Nimiritsky, P. P., Sagaradze, G. D., Efimenko, A. Yu., Makarevich, P. I., and Tkachuk, V. A. (2018) The stem cell niche, Tsitologiya, 60, 575–586.CrossRefGoogle Scholar
  21. 21.
    Donnelly, H., Salmeron–Sanchez, M., and Dalby, M. J. (2018) Designing stem cell niches for differentiation and self–renewal, J. R. Soc. Interface, 15, 20180388.CrossRefGoogle Scholar
  22. 22.
    Omelyanenko, N. P., and Karpov, I. N. (2017) Patterns of cell–matrix interactions during formation the distraction bone regenerates, Bull. Exp. Biol. Med., 163, 510–514.CrossRefGoogle Scholar
  23. 23.
    Muncie, J. M., and Weaver, V. M. (2018) The physical and biochemical properties of the extracellular matrix regulate cell fate, Curr. Top. Dev. Biol., 130, 1–37.CrossRefGoogle Scholar
  24. 24.
    Chermnykh, E., Kalabusheva, E., and Vorotelyak, E. (2018) Extracellular matrix as a regulator of epidermal stem cell fate, Int. J. Mol. Sci., 19, E1003.CrossRefGoogle Scholar
  25. 25.
    Agmon, G., and Christman, K. L. (2016) Controlling stem cell behavior with decellularized extracellular matrix scaf–folds, Curr. Opin. Solid State Mater. Sci., 20, 193–201.CrossRefGoogle Scholar
  26. 26.
    Mendez–Ferrer, S., Michurina, T. V., Ferraro, F., Mazloom, A. R., MacArthur, B. D., Lira, S. A., Scadden, D. T., Ma’ayan, A., Enikolopov, G. N., and Frenette, P. S. (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche, Nature, 466, 829–834.CrossRefGoogle Scholar
  27. 27.
    Kfoury, Y., and Scadden, D. T. (2015) Mesenchymal cell con–tributions to the stem cell niche, Cell Stem Cell, 16, 239–253.CrossRefGoogle Scholar
  28. 28.
    Humphries, J. D., Byron, A., and Humphries, M. J. (2006) Integrin ligands at a glance, J. Cell Sci., 119, 3901–3903.CrossRefGoogle Scholar
  29. 29.
    Geiger, T., and Zaidel–Bar, R. (2012) Opening the flood–gates: proteomics and the integrin adhesome, Curr. Opin. Cell Biol., 24, 562–568.CrossRefGoogle Scholar
  30. 30.
    Zhou, Z., Qu, J., He, L., Peng, H., Chen, P., and Zhou, Y. (2018) α6–Integrin alternative splicing: distinct cytoplas–mic variants in stem cell fate specification and niche inter–action, Stem Cell Res. Ther., 9, 122.CrossRefGoogle Scholar
  31. 31.
    Fujiwara, H., Ferreira, M., Donati, G., Marciano, D. K., Linton, J. M., Sato, Y., Hartner, A., Sekiguchi, K., Reichardt, L. F., and Watt, F. M. (2011) The basement membrane of hair follicle stem cells is a muscle cell niche, Cell, 144, 577–589.CrossRefGoogle Scholar
  32. 32.
    Yamada, T., Hasegawa, S., Miyachi, K., Date, Y., Inoue, Y., Yagami, A., Arima, M., Iwata, Y., Yamamoto, N., Nakata, S., Matsunaga, K., Sugiura, K., and Akamatsu, H. (2018) Laminin–332 regulates differentia–tion of human interfollicular epidermal stem cells, Mech Ageing Dev., 171, 37–46.CrossRefGoogle Scholar
  33. 33.
    Elbediwy, A., Vincent–Mistiaen, Z. I., and Thompson, B. J. (2016) YAP and TAZ in epithelial stem cells: a sensor for cell polarity, mechanical forces and tissue damage, Bioessays, 38, 644–653.CrossRefGoogle Scholar
  34. 34.
    Kuang, S., Kuroda, K., ·Le Grand, F., and Rudnicki, M. A. (2007) Asymmetric self–renewal and commitment of satel–lite stem cells in muscle, Cell, 129, 999–1010.CrossRefGoogle Scholar
  35. 35.
    Desgrosellier, S., Lesperance, J., Seguin, L., Gozo, M., Kato, S., Franovic, A., Yebra, M., Shattil, S. J., and Cheresh, D. A. (2014) Integrin αvβ3 drives Slug activation and stemness in the pregnant and neoplastic mammary gland, Dev. Cell, 30, 295–308.CrossRefGoogle Scholar
  36. 36.
    Barros, C. S., Franco, S. J., and Muller, U. (2011) Extracellular matrix: functions in the nervous system, Cold Spring Harb. Perspect. Biol., 3, a005108.Google Scholar
  37. 37.
    Gu, Y., Zhu, J., Xue, C., Li, Z., Ding, F., Yang, Y., and Gu, X. (2014) Chitosan/silk fibroin–based, Schwann cell–derived extracellular matrix–modified scaffolds for bridging rat sciatic nerve gaps, Biomaterials, 35, 2253–2263.Google Scholar
  38. 38.
    Saghatelyan, A., De Chevigny, A., Schachner, M., and Lledo, P. M. (2004) Tenascin–R mediates activity–depend–ent recruitment of neuroblasts in the adult mouse forebrain, Nat. Neurosci., 7, 347–356.CrossRefGoogle Scholar
  39. 39.
    Gilbert, P. M., Havenstrite, K. L., Magnusson, K. E. G., Sacco, A., Leonardi, N. A., Kraft, P., Nguyen, N. K., Thrun, S., Lutolf, M. P., and Blau, H. M. (2010) Substrate elasticity regulates skeletal muscle stem cell self–renewal in culture, Science, 329, 1078–1081.CrossRefGoogle Scholar
  40. 40.
    Swift, J., Ivanovska, I. L., Buxboim, A., Harada, T., Dingal, P. D. P., Pinter, J., Pajerowski, J. D., Spinler, K. R., Shin, J.–W., Tewari, M., Rehfeldt, F., Speicher, D. W., and Rehfeldt, F. (2013) Nuclear lamin–A scales with tissue stiff–ness and enhances matrix–directed differentiation, Science, 341, 1240104.CrossRefGoogle Scholar
  41. 41.
    Meran, L., Baulies, A., and Li, V. S. (2017) Intestinal stem cell niche: the extracellular matrix and cellular compo–nents, Stem Cells Int., 2017, 7970385.CrossRefGoogle Scholar
  42. 42.
    Mamidi, A., Prawiro, C., Seymour, P. A., de Lichtenberg, K. H., Jackson, A., Serup, P., and Semb, H. (2018) Mechanosignalling via integrins directs fate decisions of pancreatic progenitors, Nature, 564, 114–118.CrossRefGoogle Scholar
  43. 43.
    Brizzi, M. F., Tarone, G., and Defilippi, P. (2012) Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche, Curr. Opin. Cell Biol., 24, 645–651.CrossRefGoogle Scholar
  44. 44.
    Ahmed, M., and French–Constant, C. (2016) Extracellular matrix regulation of stem cell behavior, Curr. Stem Cell Rep., 2, 197–206.CrossRefGoogle Scholar
  45. 45.
    Sugawara, K., Tsuruta, D., Ishii, M., Jones, J. C., and Kobayashi, H. (2008) Laminin–332 and–511 in skin, Exp. Dermatol., 17, 473–480.CrossRefGoogle Scholar
  46. 46.
    Nowell, C. S., and Radtke, F. (2017) Corneal epithelial stem cells and their niche at a glance, J. Cell Sci., 130, 1021–1025.Google Scholar
  47. 47.
    Shapiro, I. M., Landis, W. J., and Risbud, M. V. (2015) Matrix vesicles: are they anchored exosomes? Bone, 79, 29–36.CrossRefGoogle Scholar
  48. 48.
    Narayanan, K., Kumar, S., Padmanabhan, P., Gulyas, B., Wan, A. C., and Rajendran, V. M. (2018) Lineage–specific exosomes could override extracellular matrix mediated human mesenchy–mal stem cell differentiation, Biomaterials, 182, 312–322.CrossRefGoogle Scholar
  49. 49.
    Thomas, D., O’Brien, T., and Pandit, A. (2018) Toward customized extracellular niche engineering: progress in cell–entrapment technologies, Adv. Mater., 30, doi: 10.1002/adma.201703948.Google Scholar
  50. 50.
    Klebe, R. J. (1974) Isolation of a collagen–dependent cell attachment factor, Nature, 250, 248–251.CrossRefGoogle Scholar
  51. 51.
    Timpl, R., Rohde, H., Robey, P. G., Rennard, S. I., Foidart, J. M., and Martin, G. R. (1979) Laminin–a gly–coprotein from basement membranes, J. Biol. Chem., 254, 9933–9937.Google Scholar
  52. 52.
    Takebayashi, T., Horii, T., Denno, H., Nakamachi, N., Otomo, K., Kitamura, S., Miyamoto, K., Horiuchi, T., and Ohta, Y. (2013) Human mesenchymal stem cells differenti–ate to epithelial cells when cultured on thick collagen gel, Biomed. Mater. Eng., 23, 143–153.Google Scholar
  53. 53.
    Sachenberg, E. I., Nikolaenko, N. N., and Pinaev, G. P. (2015) Spreading and actin cytoskeleton organization of cartilage and bone marrow stromal cells cocultured on var–ious extracellular matrix proteins, Cell Tissue Biol., 9, 1–8.CrossRefGoogle Scholar
  54. 54.
    Chen, X. D., Dusevich, V., Feng, J. Q., Manolagas, S. C., and Jilka, R. L. (2007) Extracellular matrix made by bone marrow cells facilitates expansion of marrow–derived mes–enchymal progenitor cells and prevents their differentiation into osteoblasts, J. Bone Miner. Res., 22, 1943–1956.CrossRefGoogle Scholar
  55. 55.
    Lai, Y., Sun, Y., Skinner, C. M., Son, E. L., Lu, Z., Tuan, R. S., Jilka, R. L., Ling, J., and Chen, X. D. (2010) Reconstitution of marrow–derived extracellular matrix ex vivo: a robust culture system for expanding large–scale high–ly functional human mesenchymal stem cells, Stem Cells Dev., 19, 1095–1107.CrossRefGoogle Scholar
  56. 56.
    Connelly, J. T., Gautrot, J. E., Trappmann, B., Tan, D. W. M., Donati, G., Huck, W. T., and Watt, F. M. (2010) Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions, Nat. Cell Biol., 12, 711–718.CrossRefGoogle Scholar
  57. 57.
    Chen, F. M., and Liu, X. (2016) Advancing biomaterials of human origin for tissue engineering, Prog. Polym. Sci., 53, 86–168.CrossRefGoogle Scholar
  58. 58.
    Wolchok, J. C., and Tresco, P. A. (2010) The isolation of cell derived extracellular matrix constructs using sacrificial open–cell foams, Biomaterials, 31, 9595–9603.CrossRefGoogle Scholar
  59. 59.
    Costa–Almeida, R., Granja, P. L., Soares, R., and Guerreiro, S. G. (2014) Cellular strategies to promote vas–cularization in tissue engineering applications, Eur. Cell Mater., 28, 51–57.CrossRefGoogle Scholar
  60. 60.
    Lu, W. D., Zhang, L., Wu, C. L., Liu, Z. G., Lei, G. Y., Liu, J., Gao, W., and Hu, Y. R. (2014) Development of an acellular tumor extracellular matrix as a three–dimensional scaffold for tumor engineering, PLoS One, 9, e103672.Google Scholar
  61. 61.
    Xing, Q., Yates, K., Tahtinen, M., Shearier, E., Qian, Z., and Zhao, F. (2014) Decellularization of fibroblast cell sheets for natural extracellular matrix scaffold preparation, Tissue Eng. Part C Methods, 21, 77–87.CrossRefGoogle Scholar
  62. 62.
    Cheng, C. W., Solorio, L. D., and Alsberg, E. (2014) Decellularized tissue and cell–derived extracellular matri–ces as scaffolds for orthopaedic tissue engineering, Biotechnol. Adv., 32, 462–484.CrossRefGoogle Scholar
  63. 63.
    Kalinina, N., Kharlampieva, D., Loguinova, M., Butenko, I., Pobeguts, O., Efimenko, A., Ageeva, L., Sharonov, G., Ischenko, D., Alekseev, D., Grigorieva, O., Sysoeva, V., Rubina, K., Lazarev, V., and Govorun, V. (2015) Characterization of secretomes provides evidence for adi–pose–derived mesenchymal stromal cells subtypes, Stem Cell Res. Ther., 6, 221.CrossRefGoogle Scholar
  64. 64.
    Konala, V. B. R., Mamidi, M. K., Bhonde, R., Das, A. K., Pochampally, R., and Pal, R. (2016) The current landscape of the mesenchymal stromal cell secretome: a new para–digm for cell–free regeneration, Cytotherapy, 18, 13–24.CrossRefGoogle Scholar
  65. 65.
    Kuznetsova, E. S., Nimiritsky, P. P., Grigorieva, O. A., Sagaradze, G. D., Rodionov, S. A., Omelyanenko, N. P., Makarevich, P. I., and Efimenko, A. Yu. (2018) Decellularized extracellular matrix of human mesenchymal stromal cells as a novel biomaterial for regenerative medicine, Hum. Gene Ther., A75–A76, doi: 10.1089/hum. 2018.29077.abstracts.Google Scholar
  66. 66.
    Shakouri–Motlagh, A., O’Connor, A. J., Brennecke, S. P., Kalionis, B., and Heath, D. E. (2017) Native and solubi–lized decellularized extracellular matrix: a critical assess–ment of their potential for improving the expansion of mes–enchymal stem cells, Acta Biomater., 55, 1–12.CrossRefGoogle Scholar
  67. 67.
    Sun, Y., Li, W., Lu, Z., Chen, R., Ling, J., Ran, Q., Jilka, R. L., and Chen, X. D. (2011) Rescuing replication and osteogenesis of aged mesenchymal stem cells by exposure to a young extracellular matrix, FASEB J., 25, 1474–1485.CrossRefGoogle Scholar
  68. 68.
    Ng, C. P., Sharif, A. R. M., Heath, D. E., Chow, J. W., Zhang, C. B., Chan–Park, M. B., Hammond, P. T., Chan, J. K. Y., and Griffith, L. G. (2014) Enhanced ex vivo expan–sion of adult mesenchymal stem cells by fetal mesenchymal stem cell ECM, Biomaterials, 35, 4046–4057.CrossRefGoogle Scholar
  69. 69.
    Burns, J. S., Kristiansen, M., Kristensen, L. P., Larsen, K. H., Nielsen, M. O., Christiansen, H., Nehlin, J., Andersen, J. S., and Kassem, M. (2011) Decellularized matrix from tumorigenic human mesenchymal stem cells promotes neovascularization with galectin–1 dependent endothelial interaction, PLoS One, 6, e21888.CrossRefGoogle Scholar
  70. 70.
    Hoshiba, T., Lu, H., Kawazoe, N., and Chen, G. (2010) Decellularized matrices for tissue engineering, Exp. Opin. Biol. Ther., 10, 1717–1728.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  • E. S. Novoseletskaya
    • 1
    • 2
  • O. A. Grigorieva
    • 1
  • A. Yu. Efimenko
    • 1
    • 2
    Email author
  • N. I. Kalinina
    • 2
  1. 1.Institute for Regenerative Medicine, Medical Research and Education CenterLomonosov Moscow State UniversityMoscowRussia
  2. 2.Lomonosov Moscow State UniversityFaculty of MedicineMoscowRussia

Personalised recommendations