Prominin-1+/CD133+ bone marrow-derived heart-resident cells suppress experimental autoimmune myocarditis.
OBJECTIVE
Experimental autoimmune myocarditis (EAM) is a CD4(+) T cell-mediated mouse model of inflammatory heart disease. Tissue-resident bone marrow-derived cells adopt different cellular phenotypes depending on the local milieu. We expanded a specific population of bone marrow-derived prominin-1-expressing progenitor cells (PPC) from healthy heart tissue, analysed their plasticity, and evaluated their capacity to protect mice from EAM and heart failure.


RESULTS
PPC were expanded from healthy mouse hearts. Analysis of CD45.1/CD45.2 chimera mice confirmed bone marrow origin of PPC. Depending on in vitro culture conditions, PPC differentiated into macrophages, dendritic cells, or cardiomyocyte-like cells. In vivo, PPC acquired a cardiac phenotype after direct injection into healthy hearts. Intravenous injection of PPC into myosin alpha heavy chain/complete Freund's adjuvant (MyHC-alpha/CFA)-immunized BALB/c mice resulted in heart-specific homing and differentiation into the macrophage phenotype. Histology revealed reduced severity scores for PPC-treated mice compared with control animals [treated with phosphate-buffered saline (PBS) or crude bone marrow at day 21 after MyHC-alpha/CFA immunization]. Echocardiography showed preserved fractional shortening and velocity of circumferential shortening in PPC but not PBS-treated MyHC-alpha/CFA-immunized mice. In vitro and in vivo data suggested that interferon-gamma signalling on PPC was critical for nitric oxide-mediated suppression of heart-specific CD4(+) T cells. Accordingly, PPC from interferon-gamma receptor-deficient mice failed to protect MyHC-alpha/CFA-immunized mice from EAM.


CONCLUSIONS
Prominin-1-expressing, heart-resident, bone marrow-derived cells combine high plasticity, T cell-suppressing capacity, and anti-inflammatory in vivo effects.
Kania
Gabriela
G
Experimental Critical Care, Department of Biomedicine, University Hospital, Hebelstrasse 20, CH-4031 Basle, Switzerland. g.kania@unibas.ch
Blyszczuk
Przemyslaw
P
Valaperti
Alan
A
Dieterle
Thomas
T
Leimenstoll
Bernd
B
Dirnhofer
Stephan
S
Zulewski
Henryk
H
Eriksson
Urs
U
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005620:Freund's Adjuvant; D006023:Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D018995:Myosin Heavy Chains; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000276:immunology*; D000096743:Interferon gamma Receptor
D000071916:AC133 Antigen; D015703:Antigens, CD; D005620:Freund's Adjuvant; D006023:Glycoproteins; D018995:Myosin Heavy Chains; D010455:Peptides; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C000606024:Prom1 protein, mouse