Skip to main content
SpringerLink
Log in

Biochemical Regulation of Regenerative Processes by Growth Factors and Cytokines: Basic Mechanisms and Relevance for Regenerative Medicine

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Regenerative medicine that had emerged as a scientific and medical discipline at end of 20th century uses cultured cells and tissue-engineered structures for transplantation into human body to restore lost or damaged organs. However, practical achievements in this field are far from the promising results obtained in laboratory experiments. Searching for new directions has made apparent that successful solution of practical problems is impossible without understanding the fundamental principles of the regulation of development, renewal, and regeneration of human tissues. These aspects have been extensively investigated by cell biologists, physiologists, and biochemists working in a specific research area often referred to as regenerative biology. It is known that during regeneration, growth factors, cytokines, and hormones act beyond the regulation of individual cell functions, but rather activate specific receptor systems and control pivotal tissue repair processes, including cell proliferation and differentiation. These events require numerous coordinated stimuli and, therefore, are practically irreproducible using single proteins or low-molecular-weight compounds, i.e., cannot be directed by applying classical pharmacological approaches. Our review summarizes current concepts on the regulatory mechanisms of renewal and regeneration of human tissues with special attention to certain general biological and evolutionary aspects. We focus on the biochemical regulatory mechanisms of regeneration, in particular, the role of growth factors and cytokines and their receptor systems. In a separate section, we discussed practical approaches for activating regeneration using small molecules and stem cell secretome containing a broad repertoire of growth factors, cytokines, peptides, and extracellular vesicles.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

EGF:

epidermal growth factor

FGF:

fibroblast growth factor

GF:

growth factor

GT:

gene therapy

HGF:

hepatocyte growth factor

IGF-1:

insulin-like growth factor-1

MSC:

mesenchymal stromal cells

PDGF:

platelet-derived growth factor

RTK:

receptor tyrosine kinase

SC:

stem cells

VEGF:

vascular endothelial growth factor.

References

  1. Goss, R. J. (1969) Principles of Regeneration, Academic Press, New York.

    Google Scholar 

  2. Wyllie, A. H. (1987) Apoptosis: cell death in tissue regulation, J. Pathol., 153, 313–316.

    Article  CAS  PubMed  Google Scholar 

  3. Guillot, C., and Lecuit, T. (2013) Mechanics of epithelial tissue homeostasis and morphogenesis, Science, 340, 1185–1189.

    Article  CAS  PubMed  Google Scholar 

  4. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. (2002) Molecular Biology of the Cell, 4th Edn., Garland Science, New York.

    Google Scholar 

  5. Iismaa, S. E., Kaidonis, X., Nicks, A. M., Bogush, N., Kikuchi, K., Naqvi, N., Harvey, R. P., Husain, A., and Graham, R. M. (2018) Comparative regenerative mechanisms across different mammalian tissues, NPJ Regen. Med., 3, 6.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Stocum, D. L. (2012) An overview of regenerative biology, in Regenerative Biology and Medicine, 2nd Edn., Academic Press, San Diego, pp. 3–20.

    Chapter  Google Scholar 

  7. Goss, R. J. (1980) Prospects of regeneration in man, Clin. Orthop. Relat. Res., 151, 270–282.

    Google Scholar 

  8. Seifert, A. W., and Muneoka, K. (2018) The blastema and epimorphic regeneration in mammals, Dev. Biol., 433, 190–199.

    Article  CAS  PubMed  Google Scholar 

  9. Bleacher, J. C., Adolph, V. R., Dillon, P. W., and Krummel, T. M. (1993) Fetal tissue repair and wound healing, Dermatol. Clin., 11, 677–683.

    Article  CAS  PubMed  Google Scholar 

  10. Dostal, G. H., and Gamelli, R. L. (1993) Fetal wound healing, Surg. Gynecol. Obstet., 176, 299–306.

    CAS  PubMed  Google Scholar 

  11. Burrington, J. D. (1971) Wound healing in the fetal lamb, J. Pediatr. Surg., 6, 523–528.

    Article  CAS  PubMed  Google Scholar 

  12. Frantz, F. W., Diegelmann, R. F., Mast, B. A., and Cohen, I. K. (1992) Biology of fetal wound healing: collagen biosynthesis during dermal repair, J. Pediatr. Surg., 27, 945–948.

    Article  CAS  PubMed  Google Scholar 

  13. Buonocore, G., Perrone, S., and Tataranno, M. L. (2017) Oxidative stress in the newborn, Oxid. Med. Cell. Longev., 2017, 1094247.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Torres-Cuevas, I., Parra-Llorca, A., Sanchez-Illana, A., Nunez-Ramiro, A., Kuligowski, J., Chafer-Pericas, C., Cernada, M., Escobar, J., and Vento, M. (2017) Oxygen and oxidative stress in the perinatal period, Redox. Biol., 12, 674–681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yun, M. H. (2015) Changes in regenerative capacity through lifespan, Int. J. Mol. Sci., 16, 25392–25432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nakada, Y., Canseco, D. C., Thet, S., Abdisalaam, S., Asaithamby, A., Santos, C. X., Shah, A. M., Zhang, H., Faber, J. E., Kinter, M. T., Szweda, L. I., Xing, C., Hu, Z., Deberardinis, R. J., Schiattarella, G., Hill, J. A., Oz, O., Lu, Z., Zhang, C. C., Kimura, W., and Sadek, H. A. (2017) Hypoxia induces heart regeneration in adult mice, Nature, 541, 222–227.

    Article  CAS  PubMed  Google Scholar 

  17. Simkin, J., and Seifert, A. W. (2018) Concise review: translating regenerative biology into clinically relevant therapies: are we on the right path? Stem Cells Transl. Med., 7, 220–231.

    Article  PubMed  Google Scholar 

  18. Gawriluk, T. R., Simkin, J., Thompson, K. L., Biswas, S. K., Clare-Salzler, Z., Kimani, J. M., Kiama, S. G., Smith, J. J., Ezenwa, V. O., and Seifert, A. W. (2016) Comparative analysis of ear-hole closure identifies epimorphic regeneration as a discrete trait in mammals, Nat. Commun., 7, 11164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Christ, G. J., Saul, J. M., Furth, M. E., and Andersson, K. E. (2013) The pharmacology of regenerative medicine, Pharmacol. Rev., 65, 1091–1133.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Tanaka, E. M., and Reddien, P. W. (2011) The cellular basis for animal regeneration, Dev. Cell, 21, 172–185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nimiritsky, P. P., Eremichev, R. Y., Alexandrushkina, N. A., Efimenko, A. Y., Tkachuk, V. A., and Makarevich, P. I. (2019) Unveiling mesenchymal stromal cells’ organizing function in regeneration, Int. J. Mol. Sci., 20, E823, doi: https://doi.org/10.3390/ijms20040823.

    Article  PubMed  CAS  Google Scholar 

  22. Nimiritsky, P. P., Sagaradze, G. D., Efimenko, A. Y., Makarevich, P. I., and Tkachuk, V. A. (2018) The stem cell niche, Tsitologiya, 60, 575–586.

    Article  Google Scholar 

  23. Mazzarello, P. (1999) A unifying concept: the history of cell theory, Nat. Cell Biol., 1, E13–E15.

    Article  CAS  PubMed  Google Scholar 

  24. Shay, J. W., and Wright, W. E. (2000) Hayflick, his limit, and cellular ageing, Nat. Rev. Mol. Cell Biol., 1, 72–76.

    Article  CAS  PubMed  Google Scholar 

  25. Munoz-Espin, D., and Serrano, M. (2014) Cellular sensecence: from physiology to pathology, Nat. Rev. Mol. Cell Biol., 15, 482–496.

    Article  CAS  PubMed  Google Scholar 

  26. Klochendler, A., Weinberg-Corem, N., Moran, M., Swisa, A., Pochet, N., Savova, V., Vikesa, J., Van de Peer, Y., Brandeis, M., Regev, A., Nielsen, F. C., Dor, Y., and Eden, A. (2012) A transgenic mouse marking live replicating cells reveals in vivo transcriptional program of proliferation, Dev. Cell, 23, 681–690.

    Article  CAS  PubMed  Google Scholar 

  27. Brockes, J. P., and Kumar, A. (2008) Comparative aspects of animal regeneration, Annu. Rev. Cell Dev. Biol., 24, 525–549.

    Article  CAS  PubMed  Google Scholar 

  28. Wang, W. E., Li, L., Xia, X., Fu, W., Liao, Q., Lan, C., Yang, D., Chen, H., Yue, R., Zeng, C., Zhou, L., Zhou, B., Duan, D. D., Chen, X., Houser, S. R., and Zeng, C. (2017) Dedifferentiation, proliferation, and redifferentiation of adult mammalian cardiomyocytes after ischemic injury, Circulation, 136, 834–848.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jopling, C., Sleep, E., Raya, M., Marti, M., Raya, A., and Izpisua Belmonte, J. C. (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation, Nature, 464, 606–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Takahashi, K. (2014) Cellular reprogramming, Cold Spring Harb. Perspect. Biol., 6, a018606, doi: https://doi.org/10.1101/cshperspect.a018606.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Kelaini, S., Cochrane, A., and Margariti, A. (2014) Direct reprogramming of adult cells: avoiding the pluripotent state, Stem Cells Cloning, 7, 19–29.

    PubMed  PubMed Central  Google Scholar 

  32. Criscimanna, A., Speicher, J. A., Houshmand, G., Shiota, C., Prasadan, K., Ji, B., Logsdon, C. D., Gittes, G. K., and Esni, F. (2011) Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice, Gastroenterology, 141, 1451–1462, doi: https://doi.org/10.1053/j.gastro.2011.07.003.

    Article  CAS  PubMed  Google Scholar 

  33. Beer, R. L., Parsons, M. J., and Rovira, M. (2016) Centroacinar cells: at the center of pancreas regeneration, Dev. Biol., 413, 8–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Raven, A., Lu, W. Y., Man, T. Y., Ferreira-Gonzalez, S., O’Duibhir, E., Dwyer, B. J., Thomson, J. P., Meehan, R. R., Bogorad, R., Koteliansky, V., Kotelevtsev, Y., Ffrench-Constant, C., Boulter, L., and Forbes, S. J. (2017) Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration, Nature, 547, 350–354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Malato, Y., Naqvi, S., Schurmann, N., Ng, R., Wang, B., Zape, J., Kay, M. A., Grimm, D., and Willenbring, H. (2011) Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration, J. Clin. Invest., 121, 4850–4860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Discher, D. E., Mooney, D. J., and Zandstra, P. W. (2009) Growth factors, matrices, and forces combine and control stem cells, Science, 324, 1673–1677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Michalopoulos, G. K. (1990) Liver regeneration: molecular mechanisms of growth control, FASEB J., 4, 176–187.

    Article  CAS  PubMed  Google Scholar 

  38. Michalopoulos, G. K., and DeFrances, M. C. (1997) Liver regeneration, Science, 276, 60–66.

    Article  CAS  PubMed  Google Scholar 

  39. Tkachuk, V. A. (1994) Physiology of endocrine system, Usp. Fiziol. Nauk, 25, 47–54.

    CAS  PubMed  Google Scholar 

  40. Tkachuk, V. A. (1987) A role and place for cyclic nucleotides in neuroendocrine regulation in cells and tissues, Nauchnye Doki. Vyss. Shkoly Biol. Nauki, 6, 5–17.

    Google Scholar 

  41. Tkachuk, V. A., Vorotnikov, A. V., and Tyurin-Kuz’min, P. A. (2017) Basics of Molecular Endocrinology: Sensing and Intracellular Signaling [in Russian], GEOTAR-Media, Moscow.

    Google Scholar 

  42. Grigorian, G. Y., Mirzapoyazova, T. Y., Resink, T. J., Danilov, S. M., and Tkachuk, V. A. (1989) Regulation of phosphoinositide turnover in endothelium from human pulmonary artery, aorta and umbilical vein. Antagonistic action on the beta-adrenoceptor coupled adenylate cyclase system, J. Mol. Cell. Cardiol., 21 (Suppl. 1), 119–123.

    Article  PubMed  Google Scholar 

  43. Tkachuk, V. A. (2000) Membrane receptors and intracellular calcium, Membr. Cell Biol., 13, 263–285.

    CAS  PubMed  Google Scholar 

  44. Tkachuk, V. A., and Avakyan, A. E. (2003) Molecular mechanisms for coupling G-proteins to membrane recaptors and secondary messenger systems, Ross. Fiziol. Zh. I. M. Sechenova, 89, 1478–1490.

    CAS  Google Scholar 

  45. Tkachuk, V. A. (1982) Regulation of adenylate cyclase by hormones and guanine nucleotides in normal, desensitized, and resensitized rabbit heart, Adv. Myocardiol., 3, 305–316.

    Article  CAS  PubMed  Google Scholar 

  46. Tkachuk, V. A. (1989) Developing hormone-triggered desensitization and hypersensitivity in cardiac adenylate cyclase, Kardiologiya, 29, 122–125.

    CAS  PubMed  Google Scholar 

  47. Tkachuk, V. A., Rybin, V. O., and Nikashin, A. V. (1994) Steroid and thyroid hormones in regulating G-proteins linking membrane receptors to the secondary messenger systems, Dokl. Ross. Akad. Med. Nauk, No. 12, 7–12.

    Google Scholar 

  48. Evans, R. M., and Mangelsdorf, D. J. (2014) Nuclear receptors, RXR, and the big bang, Cell, 157, 255–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sysoeva, V. Y., Ageeva, L. V., Tyurin-Kuzmin, P. A., Sharonov, G. V., Dyikanov, D. T., Kalinina, N. I., and Tkachuk, V. A. (2017) Local angiotensin II promotes adipogenic differentiation of human adipose tissue mesenchymal stem cells through type 2 angiotensin receptor, Stem Cell Res., 25, 115–122.

    Article  CAS  PubMed  Google Scholar 

  50. Tyurin-Kuzmin, P. A., Chechekhin, V. I., Ivanova, A. M., Dyikanov, D. T., Sysoeva, V. Y., Kalinina, N. I., and Tkachuk, V. A. (2018) Noradrenaline sensitivity is severely impaired in immortalized adipose-derived mesenchymal stem cell line, Int. J. Mol. Sci., 19, E3712, doi: https://doi.org/10.3390/ijms19123712.

    Google Scholar 

  51. Tyurin-Kuzmin, P. A., Fadeeva, J. I., Kanareikina, M. A., Kalinina, N. I., Sysoeva, V. Y., Dyikanov, D. T., Stambolsky, D. V., and Tkachuk, V. A. (2016) Activation of beta-adrenergic receptors is required for elevated alpha1A-adrenoreceptors expression and signaling in mesenchymal stromal cells, Sci. Rep., 6, 32835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tyurin-Kuzmin, P. A., Dyikanov, D. T., Fadeeva, J. I., Sysoeva, V. Y., and Kalinina, N. I. (2018) Flow cytometry analysis of adrenoceptors expression in human adiposederived mesenchymal stem/stromal cells, Sci. Data, 5, 180196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Levi-Montalcini, R., and Booker, B. (1960) Excessive growth of the sympathetic ganglia evoked by a protein isolated from mouse salivary glands, Proc. Natl. Acad. Sci. USA, 46, 373–384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cohen, S. (1962) Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal, J. Biol. Chem., 237, 1555–1562.

    CAS  PubMed  Google Scholar 

  55. Cohen, S. (2008) Origins of growth factors: NGF and EGF, J. Biol. Chem., 283, 33793–33797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lemmon, M. A., and Schlessinger, J. (2010) Cell signaling by receptor tyrosine kinases, Cell, 141, 1117–1134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hunter, T. (2015) Discovering the first tyrosine kinase, Proc. Natl. Acad. Sci. USA, 112, 7877–7882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Clayton, A. H., Walker, F., Orchard, S. G., Henderson, C., Fuchs, D., Rothacker, J., Nice, E. C., and Burgess, A. W. (2005) Ligand-induced dimer-tetramer transition during the activation of the cell surface epidermal growth factor receptor - a multidimensional microscopy analysis, J. Biol. Chem., 280, 30392–30399.

    Article  CAS  PubMed  Google Scholar 

  59. Himanen, J. P., and Nikolov, D. B. (2003) Eph signaling: a structural view, Trends Neurosci., 26, 46–51.

    Article  CAS  PubMed  Google Scholar 

  60. Fambrough, D., McClure, K., Kazlauskas, A., and Lander, E. S. (1999) Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes, Cell, 97, 727–741.

    Article  CAS  PubMed  Google Scholar 

  61. Katz, M., Amit, I., and Yarden, Y. (2007) Regulation of MAPKs by growth factors and receptor tyrosine kinases, Biochim. Biophys. Acta, 1773, 1161–1176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Goh, L. K., and Sorkin, A. (2013) Endocytosis of receptor tyrosine kinases, Cold Spring Harb. Perspect. Biol., 5, a017459.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Roskoski, R., Jr. (2012) ERK1/2 MAP kinases: structure, function, and regulation, Pharmacol. Res., 66, 105–143.

    Article  CAS  PubMed  Google Scholar 

  64. Ihle, J. N. (1995) Cytokine receptor signalling, Nature, 377, 591–594.

    Article  CAS  PubMed  Google Scholar 

  65. D’Arcangelo, D., Facchiano, F., Barlucchi, L. M., Melillo, G., Illi, B., Testolin, L., Gaetano, C., and Capogrossi, M. C. (2000) Acidosis inhibits endothelial cell apoptosis and function and induces basic fibroblast growth factor and vascular endothelial growth factor expression, Circ. Res., 86, 312–318.

    Article  PubMed  Google Scholar 

  66. Green, J., and Maor, G. (2000) Effect of metabolic acidosis on the growth hormone/IGF-I endocrine axis in skeletal growth centers, Kidney Int., 57, 2258–2267.

    Article  CAS  PubMed  Google Scholar 

  67. Conway, K., Price, P., Harding, K. G., and Jiang, W. G. (2006) The molecular and clinical impact of hepatocyte growth factor, its receptor, activators, and inhibitors in wound healing, Wound Repair Regen., 14, 2–10.

    Article  PubMed  Google Scholar 

  68. Satoh, A., and Makanae, A. (2014) Conservation of position-specific gene expression in axolotl limb skin, Zool. Sci., 31, 6–13.

    Article  CAS  Google Scholar 

  69. Makarevich, P. I., Dergilev, K. V., Tsokolaeva, Z. I., Boldyreva, M. A., Shevchenko, E. K., Gluhanyuk, E. V., Gallinger, J. O., Menshikov, M. Y., and Parfyonova, Y. V. (2018) Angiogenic and pleiotropic effects of VEGF165 and HGF combined gene therapy in a rat model of myocardial infarction, PLoS One, 13, e0197566.

    Google Scholar 

  70. Rokas, A. (2008) The molecular origins of multicellular transitions, Curr. Opin. Genet. Dev., 18, 472–478.

    Article  CAS  PubMed  Google Scholar 

  71. King, N. (2004) The unicellular ancestry of animal development, Dev. Cell, 7, 313–325.

    Article  CAS  PubMed  Google Scholar 

  72. King, N., and Carroll, S. B. (2001) A receptor tyrosine kinase from choanoflagellates: molecular insights into early animal evolution, Proc. Natl. Acad. Sci. USA, 98, 15032–15037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pincus, D., Letunic, I., Bork, P., and Lim, W. A. (2008) Evolution of the phosphotyrosine signaling machinery in premetazoan lineages, Proc. Natl. Acad. Sci. USA, 105, 9680–9684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Manning, G., Young, S. L., Miller, W. T., and Zhai, Y. (2008) The protist, Monosiga brevicollis, has a tyrosine kinase signaling network more elaborate and diverse than found in any known metazoan, Proc. Natl. Acad. Sci. USA, 105, 9674–9679.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mummery, C. L., van den Eijnden-van Raaij, A. J., Feijen, A., Freund, E., Hulskotte, E., Schoorlemmer, J., and Kruijer, W. (1990) Expression of growth factors during the differentiation of embryonic stem cells in monolayer, Dev. Biol., 142, 406–413.

    Article  CAS  PubMed  Google Scholar 

  76. Shilo, B. Z. (2005) Regulating the dynamics of EGF receptor signaling in space and time, Development, 132, 4017–4027.

    Article  CAS  PubMed  Google Scholar 

  77. Piotrowska-Nitsche, K., Perea-Gomez, A., Haraguchi, S., and Zernicka-Goetz, M. (2005) Four-cell stage mouse blastomeres have different developmental properties, Development, 132, 479–490.

    Article  CAS  PubMed  Google Scholar 

  78. Zdravkovic, T., Nazor, K. L., Larocque, N., Gormley, M., Donne, M., Hunkapillar, N., Giritharan, G., Bernstein, H. S., Wei, G., Hebrok, M., Zeng, X., Genbacev, O., Mattis, A., McMaster, M. T., Krtolica, A., Valbuena, D., Simon, C., Laurent, L. C., Loring, J. F., and Fisher, S. J. (2015) Human stem cells from single blastomeres reveal pathways of embryonic or trophoblast fate specification, Development, 142, 4010–4025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Manca, A., Capsoni, S., Di Luzio, A., Vignone, D., Malerba, F., Paoletti, F., Brandi, R., Arisi, I., Cattaneo, A., and Levi-Montalcini, R. (2012) Nerve growth factor regulates axial rotation during early stages of chick embryo development, Proc. Natl. Acad. Sci. USA, 109, 2009–2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ud-Din, S., Volk, S. W., and Bayat, A. (2014) Regenerative healing, scar-free healing and scar formation across the species: current concepts and future perspectives, Exp. Dermatol., 23, 615–619.

    Article  PubMed  Google Scholar 

  81. Bielefeld, K. A., Amini-Nik, S., and Alman, B. A. (2013) Cutaneous wound healing: recruiting developmental pathways for regeneration, Cell. Mol. Life Sci., 70, 2059–2081.

    Article  CAS  PubMed  Google Scholar 

  82. Kalinina, N. I., Sysoeva, V. Y., Rubina, K. A., Parfenova, Y. V., and Tkachuk, V. A. (2011) Mesenchymal stem cells in tissue growth and repair, Acta Naturae, 3, 30–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Takeo, M., Lee, W., and Ito, M. (2015) Wound healing and skin regeneration, Cold Spring Harb. Perspect. Med., 5, a023267.

    Google Scholar 

  84. Makanae, A., Mitogawa, K., and Satoh, A. (2016) Cooperative inputs of Bmp and Fgf signaling induce tail regeneration in urodele amphibians, Dev. Biol., 410, 45–55.

    Article  PubMed  CAS  Google Scholar 

  85. Makanae, A., Hirata, A., Honjo, Y., Mitogawa, K., and Satoh, A. (2013) Nerve independent limb induction in axolotls, Dev. Biol., 381, 213–226.

    Article  CAS  PubMed  Google Scholar 

  86. Makanae, A., Mitogawa, K., and Satoh, A. (2014) Implication of two different regeneration systems in limb regeneration, Regeneration (Oxf.), 1, 1–9.

    Article  Google Scholar 

  87. Yu, L., Dawson, L. A., Yan, M., Zimmel, K., Lin, Y. L., Dolan, C. P., Han, M., and Muneoka, K. (2019) BMP9 stimulates joint regeneration at digit amputation wounds in mice, Nat. Commun., 10, 424.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Barrientos, S., Brem, H., Stojadinovic, O., and Tomic-Canic, M. (2014) Clinical application of growth factors and cytokines in wound healing, Wound Repair Regen., 22, 569–578.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Friedmann, T., and Roblin, R. (1972) Gene therapy for human genetic disease? Science, 175, 949–955.

    Article  CAS  PubMed  Google Scholar 

  90. Makarevich, P. I., and Parfyonova, Ye. V. (2017) Therapeutic angiogenesis: foundations and practical application, in Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy, Intech Open, London, pp. 343–364.

    Google Scholar 

  91. Boldyreva, M. A., Bondar, I. V., Stafeev, I. S., Makarevich, P. I., Beloglazova, I. B., Zubkova, E. S., Shevchenko, E. K., Molokotina, Y. D., Karagyaur, M. N., Ratner, E. I., and Parfyonova, Y. V. (2018) Plasmid-based gene therapy with hepatocyte growth factor stimulates peripheral nerve regeneration after traumatic injury, Biomed. Pharmacother., 101, 682–690.

    Article  CAS  Google Scholar 

  92. Makarevich, P. I., Rubkina, K. A., Dyykanov, D. T., Tkachuk, V. A., and Parfenova, E. V. (2015) A therapeutic angiogenesis induced by growth factors: current state and perspectives, Kardiologiya, 55, 59–71.

    Article  CAS  PubMed  Google Scholar 

  93. Karagyaur, M., Dyikanov, D., Makarevich, P., Semina, E., Stambolsky, D., Plekhanova, O., Kalinina, N., and Tkachuk, V. (2015) Non-viral transfer of BDNF and uPA stimulates peripheral nerve regeneration, Biomed. Pharmacother., 74, 63–70.

    Article  CAS  PubMed  Google Scholar 

  94. Makarevich, P., Tsokolaeva, Z., Shevelev, A., Rybalkin, I., Shevchenko, E., Beloglazova, I., Vlasik, T., Tkachuk, V., and Parfyonova, Y. (2012) Combined transfer of human VEGF165 and HGF genes renders potent angiogenic effect in ischemic skeletal muscle, PLoS One, 7, e38776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Shyu, K. G., Chang, H., and Isner, J. M. (2003) Synergistic effect of angiopoietin-1 and vascular endothelial growth factor on neoangiogenesis in hypercholesterolemic rabbit model with acute hindlimb ischemia, Life Sci., 73, 563–579.

    Article  CAS  PubMed  Google Scholar 

  96. Slobodkina, E. A., Makarevich, P. I., and Dolinkin, A. O. (2018) Development of gene-therapy preparations, Biofarmatsevt. Zh., 10, 3–14.

    Google Scholar 

  97. Badat, M., and Davies, J. (2017) Gene therapy in a patient with sickle cell disease, N. Engl. J. Med., 376, 2093–2094.

    Article  PubMed  Google Scholar 

  98. Rangarajan, S., Walsh, L., Lester, W., Perry, D., Madan, B., Laffan, M., Yu, H., Vettermann, C., Pierce, G. F., Wong, W. Y., and Pasi, K. J. (2017) AAV5-factor VIII gene transfer in severe hemophilia A, N. Engl. J. Med., 377, 2519–2530.

    Article  CAS  PubMed  Google Scholar 

  99. Dunbar, C. E., High, K. A., Joung, J. K., Kohn, D. B., Ozawa, K., and Sadelain, M. (2018) Gene therapy comes of age, Science, 359, eaan4672, doi: https://doi.org/10.1126/science.aan4672.

    Article  PubMed  CAS  Google Scholar 

  100. Savukinas, U. B., Enes, S. R., Sjoland, A. A., and Westergren-Thorsson, G. (2016) Concise review: the bystander effect: mesenchymal stem cell-mediated lung repair, Stem Cells, 34, 1437–1444.

    Article  PubMed  Google Scholar 

  101. 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 adipose-derived mesenchymal stromal cells subtypes, Stem Cell Res. Ther., 6, 221.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Rolandsson Enes, S., Ahrman, E., Palani, A., Hallgren, O., Bjermer, L., Malmstrom, A., Scheding, S., Malmstrom, J., and Westergren-Thorsson, G. (2017) Quantitative proteomic characterization of lung-MSC and bone marrow-MSC using DIA-mass spectrometry, Sci. Rep., 7, 9316.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Kim, H. S., Choi, D. Y., Yun, S. J., Choi, S. M., Kang, J. W., Jung, J. W., Hwang, D., Kim, K. P., and Kim, D. W. (2012) Proteomic analysis of microvesicles derived from human mesenchymal stem cells, J. Proteome Res., 11, 839–849.

    Article  CAS  PubMed  Google Scholar 

  104. Sagaradze, G., Grigorieva, O., Nimiritsky, P., Basalova, N., Kalinina, N., Akopyan, Z., and Efimenko, A. (2019) Conditioned medium from human mesenchymal stromal cells: towards the clinical translation, Int. J. Mol. Sci., 20, E1656, doi: https://doi.org/10.3390/ijms20071656.

    Article  PubMed  CAS  Google Scholar 

  105. Phinney, D. G., and Pittenger, M. F. (2017) Concise review: MSC-derived exosomes for cell-free therapy, Stem Cells, 35, 851–858.

    Article  CAS  PubMed  Google Scholar 

  106. Bang, O. Y., and Kim, E. H. (2019) Mesenchymal stem Cell-derived extracellular vesicle therapy for stroke: challenges and progress, Front. Neurol., 10, 211.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Zubkova, E. S., Beloglazova, I. B., Makarevich, P. I., Boldyreva, M. A., Sukhareva, O. Y., Shestakova, M. V., Dergilev, K. V., Parfyonova, Y. V., and Menshikov, M. Y. (2016) Regulation of adipose tissue stem cells angiogenic potential by tumor necrosis factor-alpha, J. Cell. Biochem., 117, 180–196.

    Article  CAS  PubMed  Google Scholar 

  108. Efimenko, A., Starostina, E., Kalinina, N., and Stolzing, A. (2011) Angiogenic properties of aged adipose derived mesenchymal stem cells after hypoxic conditioning, J. Transl. Med., 9, 10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Aleksandrushkina, N. A., Danilova, N. V., Grigorieva, O. A., Mal’kov, P. G., Popov, V. S., Efimenko, A. Y., and Makarevich, P. I. (2019) Cell sheets of mesenchymal stromal cells effectively stimulate healing of deep soft tissue defects, Bull. Exp. Biol. Med., 167, 159–163.

    Article  CAS  PubMed  Google Scholar 

  110. Baertschiger, R. M., Serre-Beinier, V., Morel, P., Bosco, D., Peyrou, M., Clement, S., Sgroi, A., Kaelin, A., Buhler, L. H., and Gonelle-Gispert, C. (2009) Fibrogenic potential of human multipotent mesenchymal stromal cells in injured liver, PLoS One, 4, e6657.

    Google Scholar 

  111. Shi, S., and Gronthos, S. (2003) Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp, J. Bone Miner. Res., 18, 696–704.

    Article  PubMed  Google Scholar 

  112. Murphy, A. R., Laslett, A., O’Brien, C. M., and Cameron, N. R. (2017) Scaffolds for 3D in vitro culture of neural lineage cells, Acta Biomater., 54, 1–20.

    Article  CAS  PubMed  Google Scholar 

  113. Pourquie, O., Al Tanoury, Z., and Chal, J. (2018) The long road to making muscle in vitro, Curr. Top. Dev. Biol., 129, 123–142.

    Article  CAS  PubMed  Google Scholar 

  114. Syverud, B. C., Van Dusen, K. W., and Larkin, L. M. (2016) Growth factors for skeletal muscle tissue engineering, Cells Tissues Organs, 202, 169–179.

    Article  CAS  PubMed  Google Scholar 

  115. Cosson, S., Otte, E. A., Hezaveh, H., and Cooper-White, J. J. (2015) Concise review: tailoring bioengineered scaffolds for stem cell applications in tissue engineering and regenerative medicine, Stem Cells Transl. Med., 4, 156–164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lane, S. W., Williams, D. A., and Watt, F. M. (2014) Modulating the stem cell niche for tissue regeneration, Nat. Biotechnol., 32, 795–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Efimenko, A. Y., Kochegura, T. N., Akopyan, Z. A., and Parfyonova, Y. V. (2015) Autologous stem cell therapy: how aging and chronic diseases affect stem and progenitor cells, Biores. Open Access, 4, 26–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chacon-Martinez, C. A., Koester, J., and Wickstrom, S. A. (2018) Signaling in the stem cell niche: regulating cell fate, function and plasticity, Development, 145.

    Google Scholar 

  119. Mohamed, T. M. A., Ang, Y. S., Radzinsky, E., Zhou, P., Huang, Y., Elfenbein, A., Foley, A., Magnitsky, S., and Srivastava, D. (2018) Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration, Cell, 173, 104–116e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Huang, P., Zhang, L., Gao, Y., He, Z., Yao, D., Wu, Z., Cen, J., Chen, X., Liu, C., Hu, Y., Lai, D., Hu, Z., Chen, L., Zhang, Y., Cheng, X., Ma, X., Pan, G., Wang, X., and Hui, L. (2014) Direct reprogramming of human fibroblasts to functional and expandable hepatocytes, Cell Stem Cell, 14, 370–384.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Funding. The study was supported by the Russian Science Foundation (project 19-75-30007; manuscript preparation and providing access to source materials) and Grant of the President of the Russian Federation for Governmental Support of Young Russian Scientists (MK-1068.2019.7; figure preparation).

Author information

Authors and Affiliations

  1. Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, 119991, Moscow, Russia

    P. I. Makarevich, A. Yu. Efimenko & V. A. Tkachuk

  2. Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991, Moscow, Russia

    P. I. Makarevich, A. Yu. Efimenko & V. A. Tkachuk

  3. National Medical Research Center of Cardiology, Institute of Experimental Cardiology, 121552, Moscow, Russia

    V. A. Tkachuk

Authors
  1. P. I. Makarevich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Yu. Efimenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. A. Tkachuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. I. Makarevich.

Additional information

The article is dedicated to the 80th anniversary of the Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University (see Volume 84, Issue 11, 2019).

Conflict of interest. The authors declare no conflict of interest.

Compliance with ethical standards. The article does not contain description of studies with human subjects or animals performed by any of the authors.

Russian Text © The Author(s), 2020, published in Biokhimiya, 2020, Vol. 85, No. 1, pp. 15–33.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Makarevich, P.I., Efimenko, A.Y. & Tkachuk, V.A. Biochemical Regulation of Regenerative Processes by Growth Factors and Cytokines: Basic Mechanisms and Relevance for Regenerative Medicine. Biochemistry Moscow 85, 11–26 (2020). https://doi.org/10.1134/S0006297920010022

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297920010022

Keywords

Search

Navigation