CURRENT DIRECTIONS OF RESEARCH INTO CELLULAR MECHANISMS OF REPAIRATIVE REGENERATION

О. S. Voloshyn, V. D. Voloshyn, H. B. Humeniuk

Abstract


Tissues of the body can be damaged by a wide range of environmental factors, including injuries of various origins, infectious diseases, radiation exposure, and dystrophic, destructive, and atrophic changes. The high frequency of tissue structure disruption has led to a significant increase in research activity concerning the mechanisms and processes of reparative regeneration. This research aims to develop modern, practical approaches to optimising healing.
The present article offers an analysis of extant scholarly sources concerning contemporary aspects of the study of cellular mechanisms of reparative regeneration and possible methods of stimulating healing processes. A systematic review of contemporary scientific literature from scientometric databases and scientific search engines, including PubMed, Medscape, and Google Scholar, was conducted.
The primary theoretical and experimental studies of cellular mechanisms of reparative regeneration focus on the roles of fibroblasts, myofibroblasts, macrophages, neutrophils, lymphocytes, keratinocytes, and other cells. The functions of macrophages in pathogen clearance, removal of dead cells, and release of factors regulating the activity of fibroblasts, endothelial cells, and keratinocytes have been established, although further investigation is required to elucidate the specific features of different macrophage phenotypes. Fibroblasts have been shown to play an exceptional role in reparative regeneration, with evidence indicating their ability to activate cells of innate immunity. Collectively with myofibroblasts, they constitute the central link in tissue remodelling within the wound area, thus contributing to wound closure.
Further research is required into the mechanisms of differentiation and functioning of myofibroblasts, as well as the regulation of their apoptosis. This is of crucial importance, since excessive activation of these cells contributes to the development of fibrotic pathologies in various organs.
Furthermore, the role of neutrophils in reparative regeneration is significant due to their key involvement in inflammation. Research has demonstrated that neutrophils possess the capacity for sophisticated intercellular interactions, and their activation has been shown to significantly extend their lifespan and functional role in the healing process.
A more in-depth examination of the cellular mechanisms underpinning regeneration is intrinsically linked to the substantiation of stem cell-based therapeutic interventions. A mounting body of research is exploring the potential of utilising both stem cells and their associated exosome products.
The present state of research in the domain of cellular mechanisms of reparative regeneration is indicative of two prevailing trends. Firstly, there is a strong connection to the ongoing need for objective monitoring of tissue recovery. Secondly, there is a need to develop effective methods to stimulate reparative processes. A detailed investigation of the regenerative potential of stem cells, fibroblasts, inflammatory cells, macrophages, and endothelial cells, along with the molecular mechanisms of intercellular interactions in tissue repair, remains highly promising.

Keywords


reparative regeneration; cellular mechanisms; wound healing; inflammatory cells; fibroblasts; fibrosis.

References


Aitcheson S. M., Frentiu F. D., Hurn S. E., Edwards K., Murray R. Z. Skin wound healing: normal macrophage function and macrophage dysfunction in diabetic wounds. Molecules. 2021. Vol. 26, № 16. P. 4917. URL: https://doi.org/10.3390/molecules26164917.

Anders C. B., Lawton T. M. W., Ammons M. C. B. Metabolic immunomodulation of macrophage functional plasticity in nonhealing wounds. Current Opinion in Infectious Diseases. 2019. Vol. 32, № 3. P. 204–209. URL: https://doi.org/10.1097/QCO.0000000000000550.

Arribas-López E., Zand N., Ojo O., Snowden M. J., Kochhar T. The effect of amino acids on wound healing: a systematic review and meta-analysis on arginine and glutamine. Nutrients. 2021. Vol. 13, № 8. P. 2498. URL: https://doi.org/10.3390/nu13082498.

Bodnar R. J., Satish L., Yates C. C., Wells A. Pericytes: a newly recognized player in wound healing. Wound Repair and Regeneration. 2016. Vol. 24, № 2. P. 204–214. URL: https://doi.org/10.1111/wrr.12415.

Chang S. Y., Lee J. H., Oh S. C., Lee M. Y., Lim N. K. Human fibroblast growth factor-treated adipose-derived stem cells facilitate wound healing and revascularization in rats with diabetes mellitus. Cells. 2023. Vol. 12, № 8. P. 1146. URL: https://doi.org/10.3390/cells12081146.

Chapple I. L. C., Hirschfeld J., Kantarci A., Wilensky A., Shapira L. The role of the host-neutrophil biology. Periodontology 2000. 2023. DOI: https://doi.org/10.1111/prd.12490.

Chen Y. C., Chuang E. Y., Tu Y. K., Hsu C. L., Cheng N. C. Human platelet lysate-cultured adipose-derived stem cell sheets promote angiogenesis and accelerate wound healing via CCL5 modulation. Stem Cell Research & Therapy. 2024. Vol. 15, № 1. P. 163. URL: https://doi.org/10.1186/s13287-024-03762-9.

Darby I. A., Zakuan N., Billet F., Desmoulière A. The myofibroblast, a key cell in normal and pathological tissue repair. Cellular and Molecular Life Sciences. 2016. Vol. 73, № 6. P. 1145–1157. URL: https://doi.org/10.1007/s00018-015-2110-0.

Eming S. A., Murray P. J., Pearce E. J. Metabolic orchestration of the wound healing response. Cell Metabolism. 2021. Vol. 33, № 9. P. 1726–1743. URL: https://doi.org/10.1016/j.cmet.2021.07.017.

Eming S. A., Wynn T. A., Martin P. Inflammation and metabolism in tissue repair and regeneration. Science. 2017. Vol. 356, № 6342. P. 1026–1030. URL: https://doi.org/10.1126/science.aam7928.

Farabi B., Roster K., Hirani R., Tepper K., Atak M. F., Safai B. The efficacy of stem cells in wound healing: a systematic review. International Journal of Molecular Sciences. 2024. Vol. 25, № 5. P. 3006. URL: https://doi.org/10.3390/ijms25053006.

Fetz A. E., Radic M. Z., Bowlin G. L. Neutrophils in biomaterial-guided tissue regeneration: matrix reprogramming for angiogenesis. Tissue Engineering Part B: Reviews. 2021. Vol. 27, № 2. P. 95–106. URL: https://doi.org/10.1089/ten.TEB.2020.0028.

Fiorino E., Rossin D., Vanni R., Aubry M., Giachino C., Rastaldo R. Recent insights into endogenous mammalian cardiac regeneration post-myocardial infarction. International Journal of Molecular Sciences. 2024. Vol. 25, № 21. P. 11747. URL: https://doi.org/10.3390/ijms252111747.

Frangogiannis N. G. Cardiac fibrosis: cell biological mechanisms, molecular pathways and therapeutic opportunities. Molecular Aspects of Medicine. 2019. Vol. 65. P. 70–99. URL: https://doi.org/10.1016/j.mam.2018.07.001.

Guillamat-Prats R. The role of MSC in wound healing, scarring and regeneration. Cells. 2021. Vol. 10, № 7. P. 1729. URL: https://doi.org/10.3390/cells10071729.

Hinz B. Myofibroblasts. Experimental Eye Research. 2016. Vol. 142. P. 56–70. URL: https://doi.org/10.1016/j.exer.2015.07.009.

Hinz B. The role of myofibroblasts in wound healing. Current Research in Translational Medicine. 2016. Vol. 64, № 4. P. 171–177. URL: https://doi.org/10.1016/j.retram.2016.09.003.

Hu Y., Rao S. S., Wang Z. X., Cao J., Tan Y. J., Luo J., Li H. M., Zhang W. S., Chen C. Y., Xie H. Exosomes from human umbilical cord blood accelerate cutaneous wound healing through miR-21-3p-mediated promotion of angiogenesis and fibroblast function. Theranostics. 2018. Vol. 8, № 1. P. 169–184. URL: https://doi.org/10.7150/thno.21234.

Knoedler S., Broichhausen S., Guo R., Dai R., Knoedler L., Kauke-Navarro M., Diatta F., Pomahac B., Machens H. G., Jiang D., Rinkevich Y. Fibroblasts – the cellular choreographers of wound healing. Frontiers in Immunology. 2023. Vol. 14. P. 1233800. URL: https://doi.org/10.3389/fimmu.2023.1233800.

Lebonvallet N., Laverdet B., Misery L., Desmoulière A., Girard D. New insights into the roles of myofibroblasts and innervation during skin healing and innovative therapies to improve scar innervation. Experimental Dermatology. 2018. Vol. 27, № 9. P. 950–958. URL: https://doi.org/10.1111/exd.13681.

Li Y., Yu Y., Xie Z., Ye X., Liu X., Xu B., Mao J. Serum-derived exosomes accelerate scald wound healing in mice by optimizing cellular functions and promoting Akt phosphorylation. Biotechnology Letters. 2021. Vol. 43, № 8. P. 1675–1684. URL: https://doi.org/10.1007/s10529-021-03148-4.

Liu P., Shen W. Q., Chen H. L. Efficacy of arginine-enriched enteral formulas for the healing of pressure ulcers: a systematic review. Journal of Wound Care. 2017. Vol. 26, № 6. P. 319–323. URL: https://doi.org/10.12968/jowc.2017.26.6.319.

Lurje I., Gaisa N. T., Weiskirchen R., Tacke F. Mechanisms of organ fibrosis: emerging concepts and implications for novel treatment strategies. Molecular Aspects of Medicine. 2023. Vol. 92. P. 101191. URL: https://doi.org/10.1016/j.mam.2023.101191.

Majeed A. A., Abood D. A. Histological assessment of the efficiency of rabbit serum in healing skin wounds. Veterinary World. 2019. Vol. 12, № 10. P. 1650–1656. URL: https://doi.org/10.14202/vetworld.2019.1650-1656.

Marconi G. D., Fonticoli L., Rajan T. S., Pierdomenico S. D., Trubiani O., Pizzicannella J., Diomede F. Epithelial-mesenchymal transition (EMT): the type-2 EMT in wound healing, tissue regeneration and organ fibrosis. Cells. 2021. Vol. 10, № 7. P. 1587. URL: https://doi.org/10.3390/cells10071587.

Martín-Bórnez M., Falcón D., Morrugares R., Siegfried G., Khatib A. M., Rosado J. A., Galeano-Otero I., Smani T. New insights into the reparative angiogenesis after myocardial infarction. International Journal of Molecular Sciences. 2023. Vol. 24, № 15. P. 12298. URL: https://doi.org/10.3390/ijms241512298.

Mazini L., Rochette L., Admou B., Amal S., Malka G. Hopes and limits of adipose-derived stem cells (ADSCs) and mesenchymal stem cells (MSCs) in wound healing. International Journal of Molecular Sciences. 2020. Vol. 21, № 4. P. 1306. URL: https://doi.org/10.3390/ijms21041306.

Morikawa S., Iribar H., Gutiérrez-Rivera A., Ezaki T., Izeta A. Pericytes in cutaneous wound healing. Advances in Experimental Medicine and Biology. 2019. Vol. 1147. P. 1–63. URL: https://doi.org/10.1007/978-3-030-16908-4_1.

Nourian Dehkordi A., Mirahmadi Babaheydari F., Chehelgerdi M., Raeisi Dehkordi S. Skin tissue engineering: wound healing based on stem-cell-based therapeutic strategies. Stem Cell Research & Therapy. 2019. Vol. 10, № 1. P. 111. URL: https://doi.org/10.1186/s13287-019-1212-2.

Pakshir P., Hinz B. The big five in fibrosis: macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biology. 2018. Vol. 68–69. P. 81–93. URL: https://doi.org/10.1016/j.matbio.2018.01.019.

Rathinam V. A. K., Chan F. K. Inflammasome, inflammation, and tissue homeostasis. Trends in Molecular Medicine. 2018. Vol. 24, № 3. P. 304–318. URL: https://doi.org/10.1016/j.molmed.2018.01.004.

Rousselle P., Montmasson M., Garnier C. Extracellular matrix contribution to skin wound re-epithelialization. Matrix Biology. 2019. Vol. 75–76. P. 12–26. URL: https://doi.org/10.1016/j.matbio.2018.01.002.

Sarrazy V., Billet F., Micallef L., Coulomb B., Desmoulière A. Mechanisms of pathological scarring: role of myofibroblasts and current developments. Wound Repair and Regeneration. 2011. Vol. 19, № 1. P. S10–S15. URL: https://doi.org/10.1111/j.1524-475X.2011.00708.x.

Schlundt C., Fischer H., Bucher C. H., Rendenbach C., Duda G. N., Schmidt-Bleek K. The multifaceted roles of macrophages in bone regeneration: a story of polarization, activation and time. Acta Biomaterialia. 2021. Vol. 133. P. 46–57. URL: https://doi.org/10.1016/j.actbio.2021.04.052.

Schuster R., Younesi F., Ezzo M., Hinz B. The role of myofibroblasts in physiological and pathological tissue repair. Cold Spring Harbor Perspectives in Biology. 2023. Vol. 15, № 1. P. a041231. URL: https://doi.org/10.1101/cshperspect.a041231.

Son B., Kim M., Won H., Jung A., Kim J., Koo Y., Lee N. K., Baek S. H., Han U., Park C. G., Shin H., Gweon B., Joo J., Park H. H. Secured delivery of basic fibroblast growth factor using human serum albumin-based protein nanoparticles for enhanced wound healing and regeneration. Journal of Nanobiotechnology. 2023. Vol. 21, № 1. P. 310. URL: https://doi.org/10.1186/s12951-023-02053-4.

Sotnichenko A. S., Gilevich I. V., Melkonyan K. I., Yutskevich Y. A., Rusinova T. V., Karakulev A. V., Bogdanov S. B., Aladina V. A., Belich Y. A., Gumenyuk S. E., Ushmarov D. I., Bykov I. M., Redko A. N., Porhanov V. A., Alekseenko S. N. Comparative morphological characteristics of the results of implantation of decellularized and recellularized porcine skin scaffolds. Bulletin of Experimental Biology and Medicine. 2021. Vol. 170, № 3. P. 378–383. URL: https://doi.org/10.1007/s10517-021-05071-0.

Sousa A. B., Barbosa J. N. The role of neutrophils in biomaterial-based tissue repair: shifting paradigms. Journal of Functional Biomaterials. 2023. Vol. 14, № 6. P. 327. URL: https://doi.org/10.3390/jfb14060327.

Talbott H. E., Mascharak S., Griffin M., Wan D. C., Longaker M. T. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell. 2022. Vol. 29, № 8. P. 1161–1180. URL: https://doi.org/10.1016/j.stem.2022.07.006.

Torsy T., Tency I., Beeckman D., Isoherranen K., Litchford M., De Vylder F. The role of glutamine and arginine in wound healing of pressure ulcers: a systematic review. Wound Repair and Regeneration. 2025. Vol. 33, № 4. P. e70077. URL: https://doi.org/10.1111/wrr.70077.

Waugh H. V., Sherratt J. A. Macrophage dynamics in diabetic wound healing. Bulletin of Mathematical Biology. 2006. Vol. 68, № 1. P. 197–207. URL: https://doi.org/10.1007/s11538-005-9022-3.

Weiskirchen R., Weiskirchen S., Tacke F. Organ and tissue fibrosis: molecular signals, cellular mechanisms and translational implications. Molecular Aspects of Medicine. 2019. Vol. 65. P. 2–15. URL: https://doi.org/10.1016/j.mam.2018.06.003.

Wu X., Reboll M. R., Korf-Klingebiel M., Wollert K. C. Angiogenesis after acute myocardial infarction. Cardiovascular Research. 2021. Vol. 117, № 5. P. 1257–1273. URL: https://doi.org/10.1093/cvr/cvaa287.

Xu Z., Zhou T., Wang Y., Zhu L., Tu J., Xu Z., Li L., Li Y. Integrated PPI- and WGCNA-retrieval of hub gene signatures for soft substrates inhibition of human fibroblasts proliferation and differentiation. Aging (Albany NY). 2022. Vol. 14, № 17. P. 6957–6974. URL: https://doi.org/10.18632/aging.204258.

Xue M., Zhao R., March L., Jackson C. Dermal fibroblast heterogeneity and its contribution to the skin repair and regeneration. Advances in Wound Care (New Rochelle). 2022. Vol. 11, № 2. P. 87–107. URL: https://doi.org/10.1089/wound.2020.1287.

Zhang B., Wu Y., Mori M., Yoshimura K. Adipose-derived stem cell conditioned medium and wound healing: a systematic review. Tissue Engineering Part B: Reviews. 2022. Vol. 28, № 4. P. 830–847. URL: https://doi.org/10.1089/ten.TEB.2021.0100.

Zhao M., Wang L., Wang M., Zhou S., Lu Y., Cui H., Racanelli A. C., Zhang L., Ye T., Ding B., Zhang B., Yang J., Yao Y. Targeting fibrosis, mechanisms and clinical trials. Signal Transduction and Targeted Therapy. 2022. Vol. 7, № 1. P. 206. URL: https://doi.org/10.1038/s41392-022-01070-3.




DOI: https://doi.org/10.25128/2078-2357.25.3.6

Refbacks

  • There are currently no refbacks.


Creative Commons Attribution 4.0 License