title: Reversion of gene expression alterations in hearts of mice with chronic chagasic cardiomyopathy after transplantation of bone marrow cells.
abstract: Chronic chagasic cardiomyopathy is a leading cause of heart failure in Latin American countries, being associated with intense inflammatory response and fibrosis. We have previously shown that bone marrow mononuclear cell (BMC) transplantation improves inflammation, fibrosis, and ventricular diameter in hearts of mice with chronic Chagas disease. Here we investigated the transcriptomic recovery induced by BMC therapy by comparing the heart transcriptomes of control, chagasic, and BMC transplanted mice. Out of the 9390 unique genes quantified in all samples, 1702 had their expression altered in chronic chagasic hearts compared to those of normal mice. Major categories of significantly upregulated genes were related to inflammation, fibrosis and immune responses, while genes involved in mitochondrion function were downregulated. When BMC-treated chagasic hearts were compared to infected mice, 96% of the alterations detected in infected hearts were restored to normal levels, although an additional 109 genes were altered by treatment. Transcriptomic recovery, a new measure that considers both resotrative and side effects of treatment, was remarkably high (84%). Immunofluorescence and morphometric analyses confirmed the effects of BMC therapy in the pattern of inflammatory-immune response and expression of adhesion molecules. In conclusion, by using large-scale gene profiling for unbiased assessment of therapeutic efficacy we demonstrate immunomodulatory effects of BMC therapy in chronic chagasic cardiomyopathy and identify potentially relevant factors involved in the pathogenesis of the disease that may provide new therapeutic targets.
authors.affiliation: Fundação Oswaldo Cruz; Salvador, Bahia, Brazil.
authors.forename: Milena B P
authors.initials: MB
authors.lastname: Soares
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Lima
authors.forename: Bruno S F
authors.initials: BS
authors.lastname: Souza
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Vasconcelos
authors.forename: Leonardo L
authors.initials: LL
authors.lastname: Rocha
authors.forename: Ricardo Ribeiro
authors.initials: RR
authors.lastname: Dos Santos
authors.forename: Sanda
authors.initials: S
authors.lastname: Iacobas
authors.forename: Regina C
authors.initials: RC
authors.lastname: Goldenberg
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Dumitru A
authors.initials: DA
authors.lastname: Iacobas
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.forename: David C
authors.initials: DC
authors.lastname: Spray
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Campos de Carvalho
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology*; D002598:Chagas Cardiomyopathy / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D037502:Galectin 3 / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D053671:Syndecan-4 / Q000235:genetics; D014349:Trypanosoma cruzi / Q000145:classification / Q000276:immunology* / Q000472:pathogenicity; D014841:von Willebrand Factor / Q000235:genetics
chemical_list: D037502:Galectin 3; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D014841:von Willebrand Factor