Injured Achilles Tendons Treated with Adipose-Derived Stem Cells Transplantation and GDF-5
Andrea Aparecida de Aro,
Giane Daniela Carneiro,
Luis Felipe R. Teodoro,
Fernanda Cristina da Veiga,
Danilo Lopes Ferrucci,
Gustavo Ferreira Simões,
Priscyla Waleska Simões,
Lúcia Elvira Alvares,
Alexandre Leite R. de Oliveira,
Cristina Pontes Vicente,
Caio Perez Gomes,
João Bosco Pesquero,
Marcelo Augusto M. Esquisatto,
Benedicto de Campos Vidal,
Edson Rosa Pimentel
Affiliations
Andrea Aparecida de Aro
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Giane Daniela Carneiro
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Luis Felipe R. Teodoro
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Fernanda Cristina da Veiga
Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Danilo Lopes Ferrucci
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Gustavo Ferreira Simões
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Priscyla Waleska Simões
Engineering, Modeling and Applied Social Sciences Center (CECS), Biomedical Engineering Graduate Program (PPGEBM), Universidade Federal do ABC (UFABC), Alameda da Universidade s/n, 09606-045 São Bernardo do Campo, SP, Brazil
Lúcia Elvira Alvares
Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Alexandre Leite R. de Oliveira
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Cristina Pontes Vicente
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Caio Perez Gomes
Department of Biophysics, Federal University of Sao Paulo–Unifesp, Pedro de Toledo, 699, 04039-032 Sao Paulo, SP, Brazil
João Bosco Pesquero
Department of Biophysics, Federal University of Sao Paulo–Unifesp, Pedro de Toledo, 699, 04039-032 Sao Paulo, SP, Brazil
Marcelo Augusto M. Esquisatto
Biomedical Sciences Graduate Program, Herminio Ometto University Center–UNIARARAS, 13607-339 Araras, SP, Brazil
Benedicto de Campos Vidal
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Edson Rosa Pimentel
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas–UNICAMP, Charles Darwin, s/n, CP 6109, 13083-970 Campinas, SP, Brazil
Tendon injuries represent a clinical challenge in regenerative medicine because their natural repair process is complex and inefficient. The high incidence of tendon injuries is frequently associated with sports practice, aging, tendinopathies, hypertension, diabetes mellitus, and the use of corticosteroids. The growing interest of scientists in using adipose-derived mesenchymal stem cells (ADMSC) in repair processes seems to be mostly due to their paracrine and immunomodulatory effects in stimulating specific cellular events. ADMSC activity can be influenced by GDF-5, which has been successfully used to drive tenogenic differentiation of ADMSC in vitro. Thus, we hypothesized that the application of ADMSC in isolation or in association with GDF-5 could improve Achilles tendon repair through the regulation of important remodeling genes expression. Lewis rats had tendons distributed in four groups: Transected (T), transected and treated with ADMSC (ASC) or GDF-5 (GDF5), or with both (ASC+GDF5). In the characterization of cells before application, ADMSC expressed the positive surface markers, CD90 (90%) and CD105 (95%), and the negative marker, CD45 (7%). ADMSC were also differentiated in chondrocytes, osteoblast, and adipocytes. On the 14th day after the tendon injury, GFP-ADMSC were observed in the transected region of tendons in the ASC and ASC+GDF5 groups, and exhibited and/or stimulated a similar genes expression profile when compared to the in vitro assay. ADMSC up-regulated Lox, Dcn, and Tgfb1 genes expression in comparison to T and ASC+GDF5 groups, which contributed to a lower proteoglycans arrangement, and to a higher collagen fiber organization and tendon biomechanics in the ASC group. The application of ADMSC in association with GDF-5 down-regulated Dcn, Gdf5, Lox, Tgfb1, Mmp2, and Timp2 genes expression, which contributed to a lower hydroxyproline concentration, lower collagen fiber organization, and to an improvement of the rats’ gait 24 h after the injury. In conclusion, although the literature describes the benefic effect of GDF-5 for the tendon healing process, our results show that its application, isolated or associated with ADMSC, cannot improve the repair process of partial transected tendons, indicating the higher effectiveness of the application of ADMSC in injured Achilles tendons. Our results show that the application of ADMSC in injured Achilles tendons was more effective in relation to its association with GDF-5.
