Contribution of mesenchymal progenitor cells to tissue repair in rat cardiac allografts undergoing chronic rejection.
BACKGROUND
Mesenchymal progenitor cells (MPC) have recently been demonstrated to actively migrate into cardiac allografts during chronic rejection. This study examines the role of MPC in tissue repair of heart allografts in a rat model of chronic rejection.


METHODS
The potential of a rat MPC line (Ap8c3) to differentiate to myofibroblasts and cardiomyocytes was studied in differentiation cultures. Ap8c3 cells tagged with an enhanced green fluorescent protein (eGFP) reporter gene were engrafted into Fischer 344 (F344) recipients of Lewis (LEW) cardiac allografts. Development of intragraft MPC into scar-forming fibroblasts and cardiomyocytes was studied using immunohistochemistry.


RESULTS
Ap8c3 cells contain fibroblast progenitors (FP) positive for P07 antibody. Transforming growth factor (TGF)-beta stimulation promoted FP to terminally differentiate into myofibroblasts, which express alpha-smooth muscle actin (alphaSMA). In cardiac differentiation culture, Ap8c3 cells were induced by 5-azatiditin (5-aza) to form tropomyosin+ myotubes, and to express mRNA encoding for cardiac troponin I (TnI) and alpha-myosin heavy chain (alphaMHC). Transfusion of eGFP+ Ap8c3 cells to F344 recipients resulted in migration of eGFP(+) cells into LEW heart allografts, as well as homing of the eGFP+ MPC to bone marrow. The majority of eGFP+ cells in the heart allografts appeared to be vimentin-expressing fibroblasts. Foci of eGFP+ myocardium were also detected in all heart allografts, with eGFP+ cardiomyocytes representing 4.8 +/- 1.2% of the allografted eGFP+ cells.


CONCLUSIONS
The data suggest that rat MPC participate in tissue repair in heart allografts by giving rise to scar-forming myofibroblasts and cardiomyocytes.
Wu
Gordon D
GD
Comprehensive Transplant Center, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. gordon.wu@cshs.org
Bowdish
Michael E
ME
Jin
Yang-Sun
YS
Zhu
Hui
H
Mitsuhashi
Noboru
N
Barsky
Lora W
LW
Barr
Mark L
ML
D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002908:Chronic Disease; D005347:Fibroblasts; D005434:Flow Cytometry; D017930:Genes, Reporter; D006084:Graft Rejection / Q000628:therapy*; D049452:Green Fluorescent Proteins; D016027:Heart Transplantation / Q000276:immunology*; D007150:Immunohistochemistry; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D032383:Myocytes, Cardiac; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D012038:Regeneration; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D049452:Green Fluorescent Proteins