Biomimetic matrices for myocardial stabilization and stem cell transplantation.
Although natural biological matrices have demonstrated modest improvement in the survival of cells transplanted into the infarcted myocardium, these materials have not been amenable to systematic optimization and therefore have limited potential to treat postinfarct cardiac injuries. Here we have developed tunable bioactive semi-interpenetrating polymer network (sIPN) hydrogels with matrix metalloproteinase (MMP) labile crosslinkers to be used as an assistive microenvironment for transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) into the infarcted myocardium. Injectable sIPN hydrogels were designed with a range of mechanical and biological properties that yielded material-dependent BMSC proliferation in vitro. Five groups were evaluated to treat myocardial infarction (MI) in adult mice: saline injection; green fluorescent protein (GFP)(+)-BMSCs delivered in saline; a sIPN matrix; a sIPN + GFP(+)-BMSCs; and Matrigel™ + GFP(+)-BMSCs. Injection of cells alone created a transient improvement in LV function that declined over time, and the synthetic hydrogel without cells resulted in the highest LV function at 6 weeks. Donor GFP-positive cells were detected after matrix-enhanced transplantation, but not without matrix support. Biomimetic sIPN hydrogel matrices succeeded both in mechanically supporting the injured myocardium and modestly enhancing donor cell survival. These matrices provide a foundation for systematic development of "pro-survival" microenvironments, and improvement in the long-term results of cardiac stem cell transplantation therapies.
Wall
Samuel T
ST
Department of Bioengineering, University of California at Berkeley, Berkeley, California, USA.
Yeh
Che-Chung
CC
Tu
Richard Y K
RY
Mann
Michael J
MJ
Healy
Kevin E
KE
D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy; D009206:Myocardium / Q000473:pathology*; D011108:Polymers / Q000138:chemical synthesis / Q000494:pharmacology; D013997:Time Factors
D001672:Biocompatible Materials; D003432:Cross-Linking Reagents; D011108:Polymers; D049452:Green Fluorescent Proteins; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D020782:Matrix Metalloproteinases