Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis
Abstract Background Leishmaniasis is a neglected disease caused by Leishmania spp. One of its characteristics is an imbalance of host immune responses to foster parasite survival. In this setting, mesenchymal stromal cells (MSCs) may be a viable therapeutic alternative, given their well-established...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-08-01
|
| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13287-020-01889-z |
| _version_ | 1818922504965586944 |
|---|---|
| author | Tadeu Diniz Ramos Johnatas Dutra Silva Alessandra Marcia da Fonseca-Martins Juliana Elena da Silveira Pratti Luan Firmino-Cruz Diogo Maciel-Oliveira Julio Souza Dos-Santos João Ivo Nunes Tenorio Almair Ferreira de Araujo Célio Geraldo Freire-de-Lima Bruno Lourenço Diaz Fernanda Ferreira Cruz Patricia Rieken Macedo Rocco Herbert Leonel de Matos Guedes |
| author_facet | Tadeu Diniz Ramos Johnatas Dutra Silva Alessandra Marcia da Fonseca-Martins Juliana Elena da Silveira Pratti Luan Firmino-Cruz Diogo Maciel-Oliveira Julio Souza Dos-Santos João Ivo Nunes Tenorio Almair Ferreira de Araujo Célio Geraldo Freire-de-Lima Bruno Lourenço Diaz Fernanda Ferreira Cruz Patricia Rieken Macedo Rocco Herbert Leonel de Matos Guedes |
| author_sort | Tadeu Diniz Ramos |
| collection | DOAJ |
| description | Abstract Background Leishmaniasis is a neglected disease caused by Leishmania spp. One of its characteristics is an imbalance of host immune responses to foster parasite survival. In this setting, mesenchymal stromal cells (MSCs) may be a viable therapeutic alternative, given their well-established immunomodulatory potential. In this study, we compared the effects of therapy with bone marrow (BM)- and adipose tissue (AD)-derived MSCs in leishmaniasis caused by Leishmania amazonensis in C57BL/6 mice. After determining the most effective MSC source, we then combined these cells with meglumine antimoniate (a pentavalent antimonial commonly used for the treatment of leishmaniasis) to treat the infected mice. Methods In vitro, co-culture of AD-MSCs and BM-MSCs with Leishmania amazonensis-infected macrophages was performed to understand the influence of both MSC sources in infected cells. In vivo, infected C57BL/6 mice were treated with phosphate-buffered saline (PBS), AD-MSCs and BM-MSCs, and then meglumine antimoniate was combined with MSCs from the most effective source. Results In vitro, co-culture of Leishmania amazonensis-infected macrophages with BM-MSCs, compared to AD-MSCs, led to a higher parasite load and lower production of nitric oxide. Fibroblasts grown in conditioned medium from co-cultures with AD-MSCs promoted faster wound healing. Despite a non-significant difference in the production of vascular endothelial growth factor, we observed higher production of tumor necrosis factor-α and interleukin (IL)-10 in the co-culture with AD-MSCs. In vivo, treatment of infected mice with BM-MSCs did not lead to disease control; however, the use of AD-MSCs was associated with partial control of lesion development, without significant differences in the parasite load. AD-MSCs combined with meglumine antimoniate reduced lesion size and parasite load when compared to PBS and AD-MSC groups. At the infection site, we detected a small production of IL-10, but we were unable to detect production of either IL-4 or interferon-γ, indicating resolution of infection without effect on the percentage of regulatory T cells. Conclusion Combination treatment of cutaneous leishmaniasis with AD-MSCs and meglumine antimoniate may be a viable alternative. |
| first_indexed | 2024-12-20T01:54:36Z |
| format | Article |
| id | doaj.art-cac448c826fc453baad5bd170af1bcc5 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-20T01:54:36Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-cac448c826fc453baad5bd170af1bcc52022-12-21T19:57:32ZengBMCStem Cell Research & Therapy1757-65122020-08-0111111510.1186/s13287-020-01889-zCombined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensisTadeu Diniz Ramos0Johnatas Dutra Silva1Alessandra Marcia da Fonseca-Martins2Juliana Elena da Silveira Pratti3Luan Firmino-Cruz4Diogo Maciel-Oliveira5Julio Souza Dos-Santos6João Ivo Nunes Tenorio7Almair Ferreira de Araujo8Célio Geraldo Freire-de-Lima9Bruno Lourenço Diaz10Fernanda Ferreira Cruz11Patricia Rieken Macedo Rocco12Herbert Leonel de Matos Guedes13Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Laboratório de Imunomodulação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Laboratório de Investigação Pulmonar, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Grupo de Imunologia e Vacinologia, Laboratório de Imunofarmacologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ)Abstract Background Leishmaniasis is a neglected disease caused by Leishmania spp. One of its characteristics is an imbalance of host immune responses to foster parasite survival. In this setting, mesenchymal stromal cells (MSCs) may be a viable therapeutic alternative, given their well-established immunomodulatory potential. In this study, we compared the effects of therapy with bone marrow (BM)- and adipose tissue (AD)-derived MSCs in leishmaniasis caused by Leishmania amazonensis in C57BL/6 mice. After determining the most effective MSC source, we then combined these cells with meglumine antimoniate (a pentavalent antimonial commonly used for the treatment of leishmaniasis) to treat the infected mice. Methods In vitro, co-culture of AD-MSCs and BM-MSCs with Leishmania amazonensis-infected macrophages was performed to understand the influence of both MSC sources in infected cells. In vivo, infected C57BL/6 mice were treated with phosphate-buffered saline (PBS), AD-MSCs and BM-MSCs, and then meglumine antimoniate was combined with MSCs from the most effective source. Results In vitro, co-culture of Leishmania amazonensis-infected macrophages with BM-MSCs, compared to AD-MSCs, led to a higher parasite load and lower production of nitric oxide. Fibroblasts grown in conditioned medium from co-cultures with AD-MSCs promoted faster wound healing. Despite a non-significant difference in the production of vascular endothelial growth factor, we observed higher production of tumor necrosis factor-α and interleukin (IL)-10 in the co-culture with AD-MSCs. In vivo, treatment of infected mice with BM-MSCs did not lead to disease control; however, the use of AD-MSCs was associated with partial control of lesion development, without significant differences in the parasite load. AD-MSCs combined with meglumine antimoniate reduced lesion size and parasite load when compared to PBS and AD-MSC groups. At the infection site, we detected a small production of IL-10, but we were unable to detect production of either IL-4 or interferon-γ, indicating resolution of infection without effect on the percentage of regulatory T cells. Conclusion Combination treatment of cutaneous leishmaniasis with AD-MSCs and meglumine antimoniate may be a viable alternative.http://link.springer.com/article/10.1186/s13287-020-01889-zLeishmaniasisMesenchymal stromal cellsAdipose tissue-derived mesenchymal stromal cellsMeglumine antimoniateBone marrow-derived mesenchymal stromal cellsParasite load |
| spellingShingle | Tadeu Diniz Ramos Johnatas Dutra Silva Alessandra Marcia da Fonseca-Martins Juliana Elena da Silveira Pratti Luan Firmino-Cruz Diogo Maciel-Oliveira Julio Souza Dos-Santos João Ivo Nunes Tenorio Almair Ferreira de Araujo Célio Geraldo Freire-de-Lima Bruno Lourenço Diaz Fernanda Ferreira Cruz Patricia Rieken Macedo Rocco Herbert Leonel de Matos Guedes Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis Stem Cell Research & Therapy Leishmaniasis Mesenchymal stromal cells Adipose tissue-derived mesenchymal stromal cells Meglumine antimoniate Bone marrow-derived mesenchymal stromal cells Parasite load |
| title | Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis |
| title_full | Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis |
| title_fullStr | Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis |
| title_full_unstemmed | Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis |
| title_short | Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis |
| title_sort | combined therapy with adipose tissue derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by leishmania amazonensis |
| topic | Leishmaniasis Mesenchymal stromal cells Adipose tissue-derived mesenchymal stromal cells Meglumine antimoniate Bone marrow-derived mesenchymal stromal cells Parasite load |
| url | http://link.springer.com/article/10.1186/s13287-020-01889-z |
| work_keys_str_mv | AT tadeudinizramos combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT johnatasdutrasilva combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT alessandramarciadafonsecamartins combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT julianaelenadasilveirapratti combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT luanfirminocruz combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT diogomacieloliveira combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT juliosouzadossantos combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT joaoivonunestenorio combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT almairferreiradearaujo combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT celiogeraldofreiredelima combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT brunolourencodiaz combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT fernandaferreiracruz combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT patriciariekenmacedorocco combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis AT herbertleoneldematosguedes combinedtherapywithadiposetissuederivedmesenchymalstromalcellsandmeglumineantimoniatecontrolslesiondevelopmentandparasiteloadinmurinecutaneousleishmaniasiscausedbyleishmaniaamazonensis |