title: A new direction for cardiac regeneration therapy: application of synergistically acting epicardium-derived cells and cardiomyocyte progenitor cells.
abstract: BACKGROUND
  Adult human epicardium-derived cells (EPDCs), transplanted into the infarcted heart, are known to improve cardiac function, mainly through paracrine protection of the surrounding tissue. We hypothesized that this effect might be further improved if these supportive EPDCs were combined with cells that could possibly supply the ischemic heart with new cardiomyocytes. Therefore, we transplanted EPDCs together with cardiomyocyte progenitor cells that can generate mature cardiomyocytes in vitro.
  
  
  RESULTS
  EPDCs and cardiomyocyte progenitor cells were isolated from human adult atrial appendages, expanded in culture, and transplanted separately or together into the infarcted mouse myocardium (total cell number, 4x10(5)). Cardiac function was determined 6 weeks later (9.4T MRI). Coculturing increased proliferation rate and production of several growth factors, indicating a mutual effect. Cotransplantation resulted in further improvement of cardiac function compared with single cell-type recipients (P<0.05), which themselves demonstrated better function than vehicle-injected controls (P<0.05). However, in contrast to our hypothesis, no graft-derived cardiomyocytes were observed within the 6-week survival, supporting that not only EPDCs but also cardiomyocyte progenitor cells acted in a paracrine manner. Because injected cell number and degree of engraftment were similar between groups, the additional functional improvement in the cotransplantation group cannot be explained by an increased amount of secreted factors but rather by an altered type of secretion.
  
  
  CONCLUSIONS
  EPDCs and cardiomyocyte progenitor cells synergistically improve cardiac function after myocardial infarction, probably instigated by complementary paracrine actions. Our results demonstrate for the first time that synergistically acting cells hold great promise for future clinical regeneration therapy.
authors.affiliation: Departments of Anatomy and Embryology, Molecular Cell Biology, and Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Winter
authors.forename: Angelique A M
authors.initials: AA
authors.lastname: van Oorschot
authors.forename: Bianca
authors.initials: B
authors.lastname: Hogers
authors.forename: Linda M
authors.initials: LM
authors.lastname: van der Graaf
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Robert E
authors.initials: RE
authors.lastname: Poelmann
authors.forename: Douwe E
authors.initials: DE
authors.lastname: Atsma
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Gittenberger-de Groot
authors.forename: Marie Jose
authors.initials: MJ
authors.lastname: Goumans
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000637:transplantation*; D000818:Animals; D020517:Atrial Appendage / Q000166:cytology / Q000637:transplantation; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000637:transplantation*; D019899:Paracrine Communication; D010496:Pericardium / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D020127:Recovery of Function; D012038:Regeneration; D044968:Regenerative Medicine; D033581:Stem Cell Transplantation; D013997:Time Factors; D016277:Ventricular Function, Left