title: Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem/progenitor cells after myocardial infarction.
abstract: Transplantation of culture-expanded adult stem/progenitor cells often results in poor cellular engraftment, survival, and migration into sites of tissue injury. Mesenchymal cells including fibroblasts and stromal cells secrete factors that protect injured tissues, promote tissue repair, and support many types of stem/progenitor cells in culture. We hypothesized that secreted factors in conditioned medium (CdM) from adult bone marrow-derived multipotent stromal cells (MSCs) could be used to prime adult cardiac stem/progenitor cells (CSCs/CPCs) and improve graft success after myocardial infarction (MI). Incubation of adult rat CPCs in CdM from human MSCs isolated by plastic adherence or by magnetic sorting against CD271 (a.k.a., p75 low-affinity nerve growth factor receptor; p75MSCs) induced phosphorylation of STAT3 and Akt in CPCs, supporting their proliferation under normoxic conditions and survival under hypoxic conditions (1% oxygen). Priming CSCs with 30× p75MSC CdM for 30 minutes prior to transplantation into subepicardial tissue 1 day after MI markedly increased engraftment compared with vehicle priming. Screening CdM with neutralizing/blocking antibodies identified connective tissue growth factor (CTGF) and Insulin as key factors in p75MSC CdM that protected CPCs. Human CTGF peptide (CTGF-D4) and Insulin synergistically promoted CPC survival during hypoxia in culture. Similar to CdM priming, priming of CSCs with CTGF-D4 and Insulin for 30 minutes prior to transplantation promoted robust engraftment, survival, and migration of CSC derivatives at 1 week and 1 month after MI. Our results indicate that short-term priming of human CSCs with CTGF-D4 and Insulin may improve graft success and cardiac regeneration in patients with MI.
authors.affiliation: Department of Medicine, Stem Cell Core and, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA; Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iso
authors.forename: Krithika S
authors.initials: KS
authors.lastname: Rao
authors.forename: Charla N
authors.initials: CN
authors.lastname: Poole
authors.forename: A K M Tarikuz
authors.initials: AK
authors.lastname: Zaman
authors.forename: Ingrid
authors.initials: I
authors.lastname: Curril
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Spees
mesh_terms: D000328:Adult; D000818:Animals; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007261:Infusions, Intra-Arterial; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D039902:Multipotent Stem Cells / Q000166:cytology; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology*; D020011:Protective Agents / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D007328:Insulin; D008024:Ligands; D020011:Protective Agents; D050796:STAT3 Transcription Factor; D055513:Connective Tissue Growth Factor; D051057:Proto-Oncogene Proteins c-akt
keywords: CSCs/CPCs; CTGF; Insulin; MSCs; Paracrine; Progenitor cells; Stem cells; Stromal cells
references.citation: J Cell Biochem. 2011 Feb;112(2):374-80
references.pmid: 21268056
references.citation: Nat Biotechnol. 2002 Sep;20(9):933-6
references.pmid: 12161760
references.citation: Circ Res. 2011 Sep 30;109(8):910-22
references.pmid: 21960724
references.citation: Blood. 2006 Aug 15;108(4):1208-15
references.pmid: 16614239
references.citation: J Biol Chem. 2009 Nov 27;284(48):33161-8
references.pmid: 19721136
references.citation: Stem Cells Transl Med. 2012 Jun;1(6):462-8
references.pmid: 23197850
references.citation: J Cell Physiol. 1977 Jun;91(3):335-44
references.pmid: 301143
references.citation: Development. 2004 May;131(9):2137-47
references.pmid: 15105373
references.citation: J Biol Chem. 2004 Mar 5;279(10):8848-55
references.pmid: 14684735
references.citation: Circ Res. 2008 Nov 21;103(11):1204-19
references.pmid: 19028920
references.citation: Stem Cells. 2004;22(7):1239-45
references.pmid: 15579642
references.citation: Cell. 2003 Sep 19;114(6):763-76
references.pmid: 14505575
references.citation: Nature. 2012 Jan 25;481(7382):457-62
references.pmid: 22281595
references.citation: Circ Res. 2004 Oct 29;95(9):911-21
references.pmid: 15472116
references.citation: Circ Res. 2011 Dec 9;109(12):1415-28
references.pmid: 22158649
references.citation: J Mol Cell Cardiol. 2008 Oct;45(4):567-81
references.pmid: 18466917
references.citation: Circulation. 2009 Sep 8;120(10):876-87
references.pmid: 19704095
references.citation: Circulation. 2005 May 17;111(19):2486-93
references.pmid: 15883216
references.citation: J Mol Cell Cardiol. 2008 May;44(5):855-64
references.pmid: 18423486
references.citation: Growth Factors. 1998;15(3):199-213
references.pmid: 9570041
references.citation: Development. 2006 Jul;133(13):2553-63
references.pmid: 16728475
references.citation: J Biochem. 1999 Jul;126(1):137-45
references.pmid: 10393331
references.citation: Circ Res. 2010 Oct 1;107(7):913-22
references.pmid: 20671238
references.citation: Exp Hematol. 2002 Jul;30(7):783-91
references.pmid: 12135677
references.citation: Cell. 2005 Jun 17;121(6):823-35
references.pmid: 15960971
references.citation: J Mol Cell Cardiol. 1998 Nov;30(11):2411-22
references.pmid: 9925376
references.citation: Blood. 1993 Apr 1;81(7):1726-38
references.pmid: 7681701
references.citation: Nature. 2010 Aug 12;466(7308):829-34
references.pmid: 20703299
references.citation: Genes Dev. 1998 Jul 1;12(13):2048-60
references.pmid: 9649508
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15242-7
references.pmid: 21876171
references.citation: Cardiovasc Res. 2008 Jan;77(1):134-42
references.pmid: 18006467
references.citation: Mol Ther. 2004 May;9(5):747-56
references.pmid: 15120336
references.citation: Haematologica. 2010 Apr;95(4):651-9
references.pmid: 20179086
references.citation: FASEB J. 2005 May;19(7):729-38
references.pmid: 15857887
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1283-8
references.pmid: 16432190
references.citation: Tissue Eng Part A. 2010 Apr;16(4):1349-61
references.pmid: 19908964
references.citation: Circulation. 2009 May 19;119(19):2587-96
references.pmid: 19414636
references.citation: Am J Physiol Cell Physiol. 2011 Aug;301(2):C272-9
references.pmid: 21613612
references.citation: J Am Soc Nephrol. 2005 Feb;16(2):340-51
references.pmid: 15601748
references.citation: Cell. 2007 Oct 19;131(2):324-36
references.pmid: 17956733
references.citation: FASEB J. 2012 Aug;26(8):3365-79
references.pmid: 22611085
references.citation: Mol Ther. 2009 Nov;17(11):1938-47
references.pmid: 19690521
references.citation: J Biol Chem. 2001 Nov 2;276(44):40659-67
references.pmid: 11518710
references.citation: J Exp Med. 2005 Jun 6;201(11):1781-91
references.pmid: 15928197
references.citation: Nat Med. 2003 Sep;9(9):1195-201
references.pmid: 12910262
references.citation: FASEB J. 2004 Mar;18(3):469-79
references.pmid: 15003992
references.citation: Circ Res. 2004 Mar 19;94(5):678-85
references.pmid: 14739163