Mesenchymal stromal cells suspended in a platelet lysate gel improve wound healing in mice

Luciana da Rosa Zinn Sostizzo; Raul Marques Rodrigues; Tuane Nerissa Alves Garcez; Victor de Mello Palma; Annelise Martins Pezzi da Silva; Vanessa de Souza Valim; Ana Helena da Rosa Paz; Anelise Bergmann Araujo; Alessandra Aparecida Paz; Lucia Silla

Authors

Luciana da Rosa Zinn Sostizzo Hospital de Clínicas de Porto Alegre – Porto Alegre (RS), Brazil. https://orcid.org/0000-0002-1721-7906
Raul Rodrigues Universidade Federal do Rio Grande do Sul, School of Medicine, Graduate Program in Medical Sciences – Porto Alegre (RS), Brazil. ,https://ror.org/041yk2d64 https://orcid.org/0000-0003-4436-2153
Tuane Nerissa Alves Garcez Hospital de Clínicas de Porto Alegre – Porto Alegre (RS), Brazil. ,https://ror.org/010we4y38 https://orcid.org/0000-0001-7226-5364
Victor de Mello Palma Universidade Federal do Rio Grande do Sul, School of Dentistry – Porto Alegre (RS), Brazil. ,https://ror.org/041yk2d64 https://orcid.org/0000-0002-8853-0270
Annelise Martins Pezzi da Silva Hospital de Clínicas de Porto Alegre – Porto Alegre (RS), Brazil. ,https://ror.org/010we4y38 https://orcid.org/0000-0002-4929-7525
Vanessa de Souza Valim Hospital de Clínicas de Porto Alegre – Porto Alegre (RS) https://orcid.org/0000-0003-1738-0807
Ana Helena da Rosa Paz Hospital de Clínicas de Porto Alegre – Porto Alegre (RS), Brazil. ,https://ror.org/010we4y38 https://orcid.org/0000-0003-3668-7054
Anelise Bergmann Araujo Hospital de Clínicas de Porto Alegre – Porto Alegre (RS), Brazil. ,https://ror.org/010we4y38 https://orcid.org/0000-0001-5277-1964
Alessandra Aparecida Paz Hospital de Clínicas de Porto Alegre – Porto Alegre (RS), Brazil. ,https://ror.org/010we4y38 https://orcid.org/0000-0001-6429-3998
Lucia Silla Hospital de Clínicas de Porto Alegre – Porto Alegre (RS), Brazil. ,https://ror.org/010we4y38 https://orcid.org/0000-0002-3892-6525

Abstract

Objective: To assess the safety and efficacy of topical wound treatment with mesenchymal stromal cells derived from bone marrow cultured and suspended in platelet lysate. Method: A prospective, interventional, controlled study was conducted with 42 C57BL/6 mice with induced excisional wounds. They were divided into four treatment groups: hydrogel (standard wound treatment), saline gel (control), platelet lysate gel, and platelet lysate gel containing mesenchymal stromal cells. Immunohistochemistry analyses were performed on day 7 (n=5) and day 13 (n=7), and safety on day 21 (n=30). Follow-up was conducted through clinical (adverse events, weight, pain, behavior, wound size reduction) and histological (healing, vascularization, collagenization) assessments. Results: Regarding safety, no adverse events or physiological changes related to the treatment were identified. The group treated with cells showed better results in wound healing through macro and microscopic assessments, followed by the platelet lysate gel group. Conclusion: The topical application of mesenchymal stromal cells was safe and showed favorable results.

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References

Lukomskyj AO, Rao N, Yan L, Pye JS, Li H, Wang B, et al. Stem cell-based tissue engineering for the treatment of burn wounds: a systematic review of preclinical studies. Stem Cell Rev Rep. 2022;18(6):1926-55. https://doi.org/10.1007/s12015-022-10341-z

Maranda E, Rodriguez-Menocal L, Badiavas E. Role of mesenchymal stem cells in dermal repair in burns and diabetic wounds. Curr Stem Cell Res Ther. 2016;12(1):61-70. https://doi.org/10.2174/1574888X11666160714115926

Jin L, Wang X, Qiao Z, Deng Y. The safety and efficacy of mesenchymal stem cell therapy in diabetic lower extremity vascular disease: a meta-analysis and systematic review. Cytotherapy. 2022;24(3):225-34. https://doi.org/10.1016/j.jcyt.2021.08.001

Torres-Guzman RA, Avila FR, Maita K, Garcia JP, De Sario GD, Borna S, et al. Mesenchymal stromal cell healing outcomes in clinical and pre-clinical models to treat pressure ulcers: a systematic review. J Clin Med. 2023;12(24):7545. https://doi.org/10.3390/jcm12247545

Oryan A, Alemzadeh E, Alemzadeh E, Barghi M, Zarei M, Salehiniya H. Effectiveness of the adipose stem cells in burn wound healing: literature review. Cell Tissue Bank. 2022;23(4):615-26. https://doi.org/10.1007/s10561-021-09961-5

Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 2014;6(5):552-70. https://doi.org/10.4252/wjsc.v6.i5.552

Zhang C, Huang L, Wang X, Zhou X, Zhang X, Li L, et al. Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: a phase I pilot study with a 3-year follow-up. Stem Cell Res Ther. 2022;13(1):451. https://doi.org/10.1186/s13287-022-03143-0

Assis A, Camargo S, Margalit R, Mitrani E. Creation of a vascular inducing device using mesenchymal stem cells to induce angiogenesis. J Biosci Bioeng. 2021;132(4):408-16. https://doi.org/10.1016/j.jbiosc.2021.06.012

Sorrell JM, Caplan AI. Topical delivery of mesenchymal stem cells and their function in wounds. Stem Cell Res Ther. 2010;1(4):30. https://doi.org/10.1186/scrt30

Rodrigues RM, Valim VS, Berger M, Silva APM, Fachel FNS, Wilke II, et al. The proteomic and particle composition of human platelet lysate for cell therapy products. J Cell Biochem. 2022;123(9):1495-505. https://doi.org/10.1002/jcb.30310

Leon JM, Driver VR, Fylling CP, Carter MJ, Anderson C, Wilson J, et al. The clinical relevance of treating chronic wounds with an enhanced near-physiological concentration of platelet-rich plasma gel. Adv Skin Wound Care. 2011;24(8):357-68. https://doi.org/10.1097/01.ASW.0000403249.85131.6f

Alvarez-Viejo M, Romero-Rosal L, Perez-Basterrechea M, García-Gala JM, Hernando-Rodriguez P, Marana-Gonzalez J, et al. Plasma-based scaffold containing bone-marrow mononuclear cells promotes wound healing in a mouse model of pressure injury. Cell Transplant. 2024;33:9636897241251619. https://doi.org/10.1177/09636897241251619

Hersant B, Sid-Ahmed M, Braud L, Jourdan M, Baba-Amer Y, Meningaud JP, et al. Platelet-rich plasma improves the wound healing potential of mesenchymal stem cells through paracrine and metabolism alterations. Stem Cells Int. 2019;2019:1234263. https://doi.org/10.1155/2019/1234263

Levoux J, Prola A, Lafuste P, Gervais M, Chevallier N, Koumaiha Z, et al. Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming. Cell Metab. 2021;33(2):283-99.e9. https://doi.org/10.1016/j.cmet.2020.12.006

Iacono E, Merlo B, Pirrone A, Antonelli C, Brunori L, Romagnoli N, et al. Effects of mesenchymal stem cells isolated from amniotic fluid and platelet-rich plasma gel on severe decubitus ulcers in a septic neonatal foal. Res Vet Sci. 2012;93(3):1439-40. https://doi.org/10.1016/j.rvsc.2012.04.008

Langford DJ, Bailey AL, Chanda ML, Clarke SE, Drummond TE, Echols S, et al. Coding of facial expressions of pain in the laboratory mouse. Nat Methods. 2010;7(6):447-9. https://doi.org/10.1038/nmeth.1455

Valim V, Amorin B, Pezzi A, Silva MAL, Alegretti AP, Silla L. Optimization of the cultivation of donor mesenchymal stromal cells for clinical use in cellular therapy. CellBio. 2014;3:25-33. http://dx.doi.org/10.4236/cellbio.2014.31003

Silla L, Valim V, Amorin B, Alegretti AP, Oliveira FS, Silva MAL, et al. A safety and feasibility study with platelet lysate expanded bone marrow mesenchymal stromal cells for the treatment of acute graft-versus-host disease in Brazil. Leuk Lymphoma. 2014;55(5):1203-5. https://doi.org/10.3109/10428194.2013.823495

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7. https://doi.org/10.1080/14653240600855905

Falanga V, Iwamoto S, Chartier M, Yufit T, Butmarc J, Kouttab N, et al. Autologous bone marrow–derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007;13(6):1299-312. https://doi.org/10.1089/ten.2006.0278

Amorim GL, Guillen MRS, Vieira PC, Barcelos LS, Borges EL. Contributions of nurses in basic research: dressing fixation model for excisional cutaneous wounds of mice. ESTIMA Braz J Enterostomal Ther. 2021;19:e1221. https://doi.org/10.30886/estima.v19.1038_IN

Galiano RD, Michaels 5th VJ, Dobryansky M, Levine JP, Gurtner GC. Quantitative and reproducible murine model of excisional wound healing. Wound Repair Regen. 2004;12(4):485-92. https://doi.org/10.1111/j.1067-1927.2004.12404.x

Sun Y, Zhao J, Zhang L, Li Z, Lei S. Effectiveness and safety of stem cell therapy for diabetic foot: a meta-analysis update. Stem Cell Res Ther. 2022;13(1):416. https://doi.org/10.1186/s13287-022-03110-9

Glenn JD, Whartenby KA. Mesenchymal stem cells: emerging mechanisms of immunomodulation and therapy. World J Stem Cells. 2014;6(5):526-39. https://doi.org/10.4252/wjsc.v6.i5.526

Silva Junior JB, Silva AAR, Melo FCC, Kumoto MC, Parca RM. Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. Special Article: Advanced therapy medicinal products in Brazil: regulatory panorama. Hematol Transfus Cell Ther. 2021;43(Suppl 2):S68-77. https://doi.org/10.1016/j.htct.2021.09.010