Evaluation of the efficacy and safety of transplantation of adipose-derived stem cells in the treatment of refractory fistulizing Crohn's disease

Authors

DOI:

https://doi.org/10.33448/rsd-v11i1.25299

Keywords:

Cell Therapy; Adipose Tissue Derived Mesenchymal Stem Cell; Crohn's Disease.

Abstract

Aim: The treatment of perianal fistulas in Crohn's disease (CD) is a challenge. Adipose-derived stem cells (ADSCs) are an option for treating fistulas, but their behavior at the injection site still needs to be further investigated. The efficacy and safety of autologous transplantation of ADSCs of patients with refractory perianal fistulizing CD was evaluated. Method: A total of 6 patients (18-48 years) were recruited. The intervention was three applications of autologous ADSCs (total of 3x107 cells). The evaluations happened in the 12th and 24th week after the first application, been considered primary and secondary efficacy outcomes, safety outcomes, anthropometric and food quality assessments. Results: Three patients completed the study and been treated 8 fistulas with ADSCs, none application-related effect was observed. The healing closure of the external part occurred in four fistulas, with local reepithelialization, and also two closed completely in the 12th week. The Van Assche index indicates improvement in only one of the patients. On the other hand, the Clinical Perianal Disease Activity Index and the quality of life assessment indicated progress for the three patients until the end of the study. By the CD Simple Endoscopic Score, two patients had the disease endoscopically inactive at the end of follow-up. Most of the anthropometric measurements were adequate and the foods that had low consumption throughout the study, in conformity for the three evaluated, were those belonging to the group of beans. Conclusion: It is concluded that autologous ADSCs have clinical potential to safely treat refractory perianal fistulizing CD.

Author Biographies

Luana Bernardi, Universidade Federal de Mato Grosso do Sul

Center for Studies in Stem Cells, Cell Therapy and Toxicological Genetics - CeTroGen, Maria Aparecida Pedrossian University Hospital - HUMAP, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.

Graduate Program in Health and Development in the Midwest Region, Dr. Hélio Mandetta Faculty of Medicine - FAMED, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.

Laynna de Carvalho Schweich-Adami, Universidade Federal de Mato Grosso do Sul

Center for Studies in Stem Cells, Cell Therapy and Toxicological Genetics - CeTroGen, Maria Aparecida Pedrossian University Hospital - HUMAP, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.

Graduate Program in Health and Development in the Midwest Region, Dr. Hélio Mandetta Faculty of Medicine - FAMED, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.

Carlos Henrique Marques dos Santos, Universidade Federal de Mato Grosso do Sul

Department of Coloproctology, University Hospital Maria Aparecida Pedrossian, Federal University of Mato Grosso do Sul, Campo Grande, MS, Brazil

Thiago Franchi Nunes, Universidade Federal de Mato Grosso do Sul

Department of Radiology, University Hospital Maria Aparecida Pedrossian, Campo Grande, MS, Brazil.

Rodrigo Juliano Oliveira, Universidade Federal de Mato Grosso do Sul

Center for Studies in Stem Cells, Cell Therapy and Toxicological Genetics - CeTroGen, Maria Aparecida Pedrossian University Hospital - HUMAP, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.

Postgraduate Program in Health and Development in the Midwest Region, Faculty of Medicine Dr. Hélio Mandetta - FAMED, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.

Postgraduate Program in Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Food and Nutrition - FACFAN, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.

Postgraduate Program in Genetics and Molecular Biology, Center for Biological Sciences - CCB, State University of Londrina, Londrina, PR, Brazil.

Andréia Conceição Millan Brochado Antoniolli-Silva, Universidade Federal de Mato Grosso do Sul

Center for Studies in Stem Cells, Cell Therapy and Toxicological Genetics - CeTroGen, Maria Aparecida Pedrossian University Hospital - HUMAP, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.


Postgraduate Program in Health and Development in the Midwest Region, Faculty of Medicine Dr. Hélio Mandetta - FAMED, Federal University of Mato Grosso do Sul - UFMS, Campo Grande, MS, Brazil.

References

Aguilera-Castro, L., Ferre-Aracil, C., Garcia-Garcia-De-Paredes, A., Rodriguez-De-Santiago, E., & Lopez-Sanroman, A (2017). Management of complex perianal Crohn’s disease. Annals of Gastroenterology, 30 (1), 33-44.

Aggarwal, S., & Pittenger, M. F. (2005). Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 105 (4), 1815-1822.

Avivar-Valderas, A., Martín-Martín, C., Ramírez, C., Del Río, B., Menta R., Mancheño-Corvo, P et al (2019). Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients. Frontiers in Immunology, 14 (10), 1244.

Almeida Filho, N., & Rouquayrol, Z. Methodological foundations of epidemiology. In: Almeida Filho, N., Barreto, ML (Org.). Epidemiology and health: fundamentals, methods and applications. 9. ed. São Paulo: Medsi, 2011.

Barreto, L. M. R. (2017). Avaliação da densidade mineral óssea e da composição corporal em portadores de doença de Crohn. [Dissertação]. Universidade Estadual de Campinas, Faculdade de Ciências Médicas, Campinas, SP.

Bislenghi, G., Wolthuis, A., Van Assche, G., Vermeire, S., Ferrante, M., & D'hoore, A (2019). Cx601 (darvadstrocel) for the treatment of perianal fistulizing Crohn's disease. Expert Opinion on Biological Therapy, 19 (7), 607-616.

Bischoff, SC., Escher, J., Hébuterne, X., Klek, S., Krznaric, Z., Schneider, S et al (2020). ESPEN practical guideline: Clinical Nutrition in inflammatory bowel disease. Clinical Nutrition, 39, 632-653.

Blackburn, G. L., & Thornton, P. A (1979). Nutritional assessment of the hospitalized patients. Medical Clinics of North Ame¬rica, 63, 1103-115.

Carvello, M., Lightner, A., Yamamoto, T., Kotze, P. G., & Spinelli, A. (2019). Mesenchymal Stem Cells for Perianal Crohn's Disease. Cells, 8 (7), 764.

Cashman, T. J., Gouon-Evans, V., & Costa, K. D. (2013). Mesenchymal stem cells for cardiac therapy: practical challenges and potential mechanisms. Stem Cell Reviews and Reports, 9 (3), 254–265.

Cho, Y. B., Park, K. J., Yoon, S. N., Song, K. H., Kim, D. S., Jung, S. H., et al (2015). Long-Term Results of Adipose-Derived Stem Cell Therapy for the Treatment of Crohn’s Fistula. Stem Cells Translational Medicine, 4 (5), 532-537.

Choi, K., Chun, J., Han, K., Park, S., Soh, H., Kim, J et al (2019). Risk of anxiety and depression in patients with inflammatory bowel disease: a national population-based study. Journal of Clinical Medicine, 8 (5), 654.

Ciccocioppo, R., Bernardo, M. E., Sgarella, A., Maccario, R., Avanzini, M. A., Ubezio, C et al (2011). Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut, 60 (6), 788-798.

Daperno, M., D'haens, G., Van Assche, G., Baert, F., Bulois, P., Maunoury, V et al (2004). Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endoscopy, 60, 505-12.

.

De Castro, M. M., Corona, L. P., Pascoal, L. B., Rodrigues, B. L., Ayrizono, M. L. S., Coy, C. S. R., et al (2019). Impaired nutritional status in outpatients in remission or with active Crohn’s disease – classified by objective endoscopic and imaging assessments. Clinical Nutrition ESPEN, 33, 60–65.

De Castro, M. M., Corona, L. P., Pascoal, L. B., Miyamoto, J. E., Ignacio-Souza, L. M., Ayrizono, M. L. S., et al (2020). Dietary Patterns Associated to Clinical Aspects in Crohn’s Disease Patients. Scientific Reports, 10, 7033.

Dominici, M., Le Blanc, K., Mueller, I et al (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy Position Statement. Cytotherapy, 8, 315–317.

Eglinton, T. W., Barclay, M. L., Gearry, R. B., & Frizelle, F. A. (2012). The spectrum of perianal Crohn’s disease in a population-based cohort. Diseases of the Colon & Rectum, 55, 773-777.

Gecse, K. B., Bemelman, W., Kamm, M. A., Stoker, J., Khanna, R., Ng, S. C., et al (2014). A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulizing Crohn's disease. Gut, 63, 1381–92.

Georgiev-Hristov, T., Guadalajara, H., Herreros, M. D., Lightner, A. L., Dozois, E. J., García-Arranz, M., et al (2018). A Step-By-Step Surgical Protocol for the Treatment of Perianal Fistula with Adipose-Derived Mesenchymal Stem Cells. Journal of Gastrointestinal Surgery, 22 (11), 2003-2012.

Ingle, S. B., & Loftus, E. V. Jr (2007). The natural history of perianal Crohn’s disease. Digestive and Liver Disease, 39, 963–969.

Karp, J. M., & Teo, G. S. L. (2009). Mesenchymal Stem Cell Homing: The Devil Is in the Details. Cell Stem Cell, 4.

Kagramanova, P., Knyazev, N., & Konoplyannikov, A (2016). The combined of mesenchymal stem cells and infliximab reduces the recurrence rate of Crohn’s disease. Journal of Crohn's and Colitis, 10 (1), 346.

Kachgal, S., &Putnam, A. J (2011). Mesenchymal stem cells from adipose and bone marrow promote angiogenesis via distinct cytokine and protease expression mechanisms. Angiogenesis, 14 (1), 47–59.

Kim, W. S., Park, B. S., Sung, J. H., Yang, J. M., Park, S. B., Kwak, S., et al (2007). Wound Healing Effect of Adipose-Derived Stem Cells: A Critical Role of Secretory Factors on Human Dermal Fibroblasts. Journal of Dermatological Science, 48 (1), 15-24.

Kreuter, R., Wankell, M., Ahlenstiel, G., & Hebbard, L (2019). The role of obesity in inflammatory bowel disease. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1865, 63–72.

Lightner, A. L., & Faubion, W. A (2017). Mesenchymal Stem Cell Injections for the Treatment of Perianal Crohn's Disease: What We Have Accomplished and What We Still Need to Do. Journal of Crohn’s & Colitis, 11 (10), 1267-1276.

Markarian, C. F., Frey, G. Z., Silveira, M. D., Chem, E. M., Milani, A. R., Ely, P. B. et al (2014). Isolation of adipose-derived stem cells: a comparison among different methods. Biotechnology Letters, 36 (4), 693-702.

Molendijk, I., Bonsing, B. A., Roelofs, H., Peeters, K. C., Wasser, M. N., dijkstra, G., et al (2015). Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients with Crohn's Disease. Gastroenterology, 149 (4), 918-927.

Ng, S. C., Shi, H. Y., Hamidi, N., Underwood, F. E., Tang, W., Benchimol, E. I., et al (2017). Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. The Lancet, 390 (10114), 2769–2778.

Ott, C., & Schölmerich, J (2013). Extraintestinal manifestations and complications in IBD. Nature Review Gastroenterology Hepatology, 10, 585–595.

Panés, J., García-Olmo, D., Van Assche, G., Colombel, J. F., Reinisch, W., Baumgart, D C., et al (2018). Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients with Crohn’s Disease. Gastroenterology, 154 (5), 334-1342.

Pesarini, J. R., Oliveira, R. J., Pessatto, L. R., Antoniolli-Silva, A. C. M. B., Felicidade, I., Nardi, N. B., et al (2017). Vitamin D: Correlation with biochemical and body composition changes in a southern Brazilian population and induction of cytotoxicity in mesenchymal stem cells derived from human adipose tissue. Biomedicine & Pharmacotherapy, 91, 861– 871.

Podojil, J. R., & Miller, S. D. (2009). Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy. Immunological Review, 229 (1), 337-355.

Rocha, R., Santana, G. O., Almeida, N., & Lyra, A. C. (2009). Analysis of fat and muscle mass in patients with inflammatory bowel disease during remission and active phase. The British Journal Nutrition, 101 (5), 676-679.

Robey, P. (2017). “Mesenchymal stem cells”: Fact or fiction, and implications in their therapeutic use. F1000 Research, 6, 1524.

Torres, J., Mehandru, S., Colombel, J. F., & Peyrin-Biroulet, L (2017). Crohn’s disease. The Lancet, 389, 1741–1755.

Van Assche, G., Vanbeckevoort, D., Bielen, D., Coremans, G., Aerden, I., Noman, M et al (2003). Magnetic resonance imaging of the effects of infliximab on perianal fistulizing Crohn’s disease. The American Journal of Gastroenterology, 98, 332–339.

World Health Organization (WHO). (1995). Physical status: the use and interpretation of anthropometry. Technical Re¬port Series, Geneva, 452 p. https://apps.who.int/iris/handle/10665/37003

World Health Organization (WHO). (1998). Obesity: preventing and managing the global epidemic. Technical Report Series, Geneva, n. 894. https://apps.who.int/iris/handle/10665/42330

Zhang, H., Zeng, Z., Mukherjee, A & Shen, B (2018). Molecular diagnosis and classification of inflammatory bowel disease. Expert Review of Molecular Diagnostics, 18 (10), 867–886.

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Published

15/01/2022

How to Cite

BERNARDI, L.; SCHWEICH-ADAMI, L. de C. .; SANTOS, C. H. M. dos; NUNES, T. F. .; OLIVEIRA, R. J. .; ANTONIOLLI-SILVA, A. C. M. B. . Evaluation of the efficacy and safety of transplantation of adipose-derived stem cells in the treatment of refractory fistulizing Crohn’s disease . Research, Society and Development, [S. l.], v. 11, n. 1, p. e575111252992, 2022. DOI: 10.33448/rsd-v11i1.25299. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/25299. Acesso em: 18 apr. 2024.

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Health Sciences