title: Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells.
abstract: BACKGROUND
  Cardiosphere-derived cells (CDCs) are an attractive cell type for tissue regeneration, and autologous CDCs are being tested clinically. However, autologous therapy necessitates patient-specific tissue harvesting and cell processing, with delays to therapy and possible variations in cell potency. The use of allogeneic CDCs, if safe and effective, would obviate such limitations. We compared syngeneic and allogeneic CDC transplantation in rats from immunologically-mismatched inbred strains.
  
  
  RESULTS
  In vitro, CDCs expressed major histocompatibility complex class I but not class II antigens or B7 costimulatory molecules. In mixed-lymphocyte cocultures, allogeneic CDCs elicited negligible lymphocyte proliferation and inflammatory cytokine secretion. In vivo, syngeneic and allogeneic CDCs survived at similar levels in the infarcted rat heart 1 week after delivery, but few syngeneic (and even fewer allogeneic) CDCs remained at 3 weeks. Allogeneic CDCs induced a transient, mild, local immune reaction in the heart, without histologically evident rejection or systemic immunogenicity. Improvements in cardiac structure and function, sustained for 6 months, were comparable with syngeneic and allogeneic CDCs. Allogeneic CDCs stimulated endogenous regenerative mechanisms (cardiomyocyte cycling, recruitment of c-kit(+) cells, angiogenesis) and increased myocardial vascular endothelial growth factor, insulin-like growth factor-1, and hepatocyte growth factor equally with syngeneic CDCs.
  
  
  CONCLUSIONS
  Allogeneic CDC transplantation without immunosuppression is safe, promotes cardiac regeneration, and improves heart function in a rat myocardial infarction model, mainly through stimulation of endogenous repair mechanisms. The indirect mechanism of action rationalizes the persistence of benefit despite the evanescence of transplanted cell survival. This work motivates the testing of allogeneic human CDCs as a potential off-the-shelf product for cellular cardiomyoplasty.
authors.affiliation: Cedars-Sinai Heart Institute, 8700 Beverly Blvd, Los Angeles, CA 90048, USA.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Malliaras
authors.forename: Tao-Sheng
authors.initials: TS
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Luthringer
authors.forename: John
authors.initials: J
authors.lastname: Terrovitis
authors.forename: Ke
authors.initials: K
authors.lastname: Cheng
authors.forename: Tarun
authors.initials: T
authors.lastname: Chakravarty
authors.forename: Giselle
authors.initials: G
authors.lastname: Galang
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Florian
authors.initials: F
authors.lastname: Schoenhoff
authors.forename: Jennifer
authors.initials: J
authors.lastname: Van Eyk
authors.forename: Linda
authors.initials: L
authors.lastname: Marbán
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006085:Graft Survival / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology / Q000637:transplantation*; D051381:Rats; D011914:Rats, Inbred BN; D011921:Rats, Inbred WKY; D018874:Spheroids, Cellular / Q000473:pathology / Q000502:physiology / Q000637:transplantation*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
references.citation: J Am Coll Cardiol. 2009 Oct 20;54(17):1619-26
references.pmid: 19833262
references.citation: Circulation. 2001 Aug 28;104(9):1046-52
references.pmid: 11524400
references.citation: Circulation. 2007 Feb 20;115(7):896-908
references.pmid: 17283259
references.citation: J Mol Cell Cardiol. 2010 Aug;49(2):312-21
references.pmid: 20211627
references.citation: Nat Med. 2002 Mar;8(3):233-9
references.pmid: 11875493
references.citation: Br Med Bull. 2011;98:161-85
references.pmid: 21652595
references.citation: Circulation. 2008 Mar 25;117(12):1555-62
references.pmid: 18332264
references.citation: Stem Cells. 2010 Nov;28(11):2088-98
references.pmid: 20882531
references.citation: Circ Res. 2008 Jun 6;102(11):1319-30
references.pmid: 18535269
references.citation: Cardiovasc Res. 2009 Jun 1;82(3):411-20
references.pmid: 19228705
references.citation: PLoS One. 2008 Apr 16;3(4):e1929
references.pmid: 18414652
references.citation: PLoS One. 2009 Sep 25;4(9):e7195
references.pmid: 19779618
references.citation: Cell Mol Life Sci. 2011 Jun;68(12):2141-56
references.pmid: 20972814
references.citation: Circ Res. 2010 Oct 1;107(7):913-22
references.pmid: 20671238
references.citation: Growth Factors. 2010 Jun;28(3):157-65
references.pmid: 20166900
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8966-71
references.pmid: 15951423
references.citation: J Am Coll Cardiol. 2014 Jan 21;63(2):110-22
references.pmid: 24036024
references.citation: Circ Res. 2010 Mar 19;106(5):971-80
references.pmid: 20110532
references.citation: Cell Stem Cell. 2011 Apr 8;8(4):389-98
references.pmid: 21474103
references.citation: Circ Res. 2009 May 22;104(10):1209-16
references.pmid: 19407239
references.citation: J Exp Med. 2007 Dec 24;204(13):3257-69
references.pmid: 18070934
references.citation: Stem Cells. 2010 May;28(5):903-4
references.pmid: 20309960
references.citation: J Am Coll Cardiol. 2011 Jan 25;57(4):455-65
references.pmid: 21251587
references.citation: Circulation. 2011 Feb 1;123(4):364-73
references.pmid: 21242485
references.citation: Cell. 2009 Jul 23;138(2):257-70
references.pmid: 19632177
references.citation: Circulation. 2009 Sep 22;120(12):1075-83, 7 p following 1083
references.pmid: 19738142
references.citation: Nat Rev Cardiol. 2010 Apr;7(4):204-15
references.pmid: 20177405
references.citation: Cardiovasc Res. 2010 Jul 1;87(1):40-9
references.pmid: 20118202
references.citation: Circ Res. 2008 Nov 21;103(11):1204-19
references.pmid: 19028920
references.citation: Circulation. 2010 Jan 19;121(2):293-305
references.pmid: 20048209
references.citation: Curr Opin Hematol. 2001 Nov;8(6):355-9
references.pmid: 11604575
references.citation: Circ Res. 2010 May 28;106(10):1570-81
references.pmid: 20378859
references.citation: J Am Coll Cardiol. 2008 Dec 2;52(23):1858-1865
references.pmid: 19038683
references.citation: Ann Thorac Surg. 2008 Jul;86(1):327-34
references.pmid: 18573459
references.citation: Am J Transplant. 2008 Feb;8(2):324-31
references.pmid: 18162086
references.citation: Stem Cells. 2009 Jul;27(7):1571-81
references.pmid: 19544463
references.citation: N Engl J Med. 2007 Jul 19;357(3):209-13
references.pmid: 17634455
references.citation: Transplantation. 2007 Mar 27;83(6):783-90
references.pmid: 17414713
references.citation: Proteomics. 2010 Jan;10(2):245-53
references.pmid: 20014349