Cell therapy enhances function of remote non-infarcted myocardium

Moreno-Gonzalez, Alicia; Korte, F. Steven; Dai, Jin; Chen, Kent; Ho, Brian; Reinecke, Hans; Murry, Charles E.; Regnier, Michael

doi:10.1016/j.yjmcc.2009.07.030

Cited by 22 publications

(36 citation statements)

References 47 publications

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“…21; and 38.5 Ϯ 9.1 mN/mm 2 in rats, ref. 25). Importantly, patches were Ϸ1,000 times less stiff than myocardial infarct scar (3730 Ϯ 1340 mN/mm 2 ) (25), suggesting that they would not inhibit diastolic filling in vivo.…”

Section: Discussionmentioning

confidence: 99%

Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue

Stevens

Kreutziger

Dupras

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

387

334

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Success of human myocardial tissue engineering for cardiac repair has been limited by adverse effects of scaffold materials, necrosis at the tissue core, and poor survival after transplantation due to ischemic injury. Here, we report the development of scaffold-free prevascularized human heart tissue that survives in vivo transplantation and integrates with the host coronary circulation. Human embryonic stem cells (hESCs) were differentiated to cardiomyocytes by using activin A and BMP-4 and then placed into suspension on a rotating orbital shaker to create human cardiac tissue patches. Optimization of patch culture medium significantly increased cardiomyocyte viability in patch centers. These patches, composed only of enriched cardiomyocytes, did not survive to form significant grafts after implantation in vivo. To test the hypothesis that ischemic injury after transplantation would be attenuated by accelerated angiogenesis, we created ''second-generation,'' prevascularized, and entirely human patches from cardiomyocytes, endothelial cells (both human umbilical vein and hESC-derived endothelial cells), and fibroblasts. Functionally, vascularized patches actively contracted, could be electrically paced, and exhibited passive mechanics more similar to myocardium than patches comprising only cardiomyocytes. Implantation of these patches resulted in 10-fold larger cell grafts compared with patches composed only of cardiomyocytes. Moreover, the preformed human microvessels anastomosed with the rat host coronary circulation and delivered blood to the grafts. Thus, inclusion of vascular and stromal elements enhanced the in vitro performance of engineered human myocardium and markedly improved viability after transplantation. These studies demonstrate the importance of including vascular and stromal elements when designing human tissues for regenerative therapies.angiogenesis ͉ human embryonic stem cells ͉ tissue engineering ͉ myocardial infarction ͉ cardiomyocyte

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Section: Discussionmentioning

confidence: 99%

Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue

Stevens

Kreutziger

Dupras

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

387

334

View full text Add to dashboard Cite

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“…[17][18][19] Briefly, scaffolds were cut into strips (0.2-0.4 mm diameter · 1.0 mm length) and mounted with aluminum foil T-clips between a force transducer and a servomotor tuned for a 300 ms step response ( Fig. 2A).…”

Section: Mechanical Stiffness and In Vitro Degradation Analysismentioning

confidence: 99%

“…19 Cardiomyocytes were separated from fibroblasts by preplating the primary cell suspension, and the two cell types were kept separately in Step length changes (4%-24%) with resulting tension measured as force (mN). (C) Normalized steady-state force (mN/mm 2 ) is plotted against % length change, and the slope of the resulting regression line is the material stiffness (kPa).…”

Section: Cell-seeding and Culture Of Fibrin Constructsmentioning

confidence: 99%

“…Cardiomyocytes were heat shocked at 42°C for 40 min, 24 h before seeding, as this has been shown to enhance cell survival after transplantation, and we believe this treatment will be important for our system due to the stress of seeding and the high density of cells being used. 19,20 Rat aortic endothelial cells (RAECs, a gift from Dr. Nicosia, VA hospital Seattle, WA) or human umbilical vein endothelial cells (HUVECs, Lonza, Basel, Switzerland) were grown in culture. For some constructs, cardiomyocytes were labeled with a fluorescent lipophilic tracer dye (CM-DiI, Vybrant Cell-Labeling Solutions; Molecular Probes, Eugene, OR) during heat shock treatment 24 h before seeding.…”

Section: Cell-seeding and Culture Of Fibrin Constructsmentioning

confidence: 99%

“…19 Scaffolds were mechanically tested in vitro to determine material stiffness and degradation rates with and without material modifications ( -FXIII, -aprotinin). The stiffness and degradation time course for each treatment tested is summarized in Figure 6 and material stiffness values are reported in Table 1.…”

Section: Acellular Scaffold Mechanical Stiffness and In Vitro Degradamentioning

confidence: 99%

See 2 more Smart Citations

Prevascularized Microtemplated Fibrin Scaffolds for Cardiac Tissue Engineering Applications

Thomson

Korte

Giachelli

et al. 2013

Tissue Engineering Part A

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Myocardial infarction (MI) causes significant cell loss and damage to myocardium. Cell-based therapies for treatment of MI aim to remuscularize the resultant scar tissue, but the majority of transplanted cells do not survive or integrate with the host tissue. Scaffolds can improve cell retention following construct implantation, but often do little to enhance host-graft integration and/or show limited biodegradation. Fibrin is an ideal biomaterial for cardiac tissue engineering as it is a natural, biodegradable polymer that can induce neovascularization, promote cell attachment, and has tunable mechanical properties. Here we describe a novel, highdensity microtemplated fibrin scaffold seeded with a tri-cell mixture of cardiomyocytes, endothelial cells (ECs), and fibroblasts to mimic native cardiac tissue in structure and cellular composition to improve cell retention and promote integration with the host tissue. Scaffolds were designed with uniform architecture of parallel 60 mm microchannels surrounded by an interconnected microporous network of 27-mm-diameter pores and mechanical stiffness comparable to native cardiac tissues (70-90kPa). Scaffold degradation was controlled with the addition of Factor XIII (FXIII) and/or protease inhibitor (aprotinin). Unmodified scaffolds had a fast degradation profile both in vitro (19.9% -3.9% stiffness retention after 10 days) and in vivo. Scaffolds treated with FXIII showed an intermediate degradation profile in vitro (45.8% -5.9%), while scaffolds treated with aprotinin or both FXIII and aprotinin showed significantly slowed degradation in vitro (60.9% -5.2% and 76.4% -7.6%, respectively, p < 0.05). Acellular aprotinin scaffold myocardial implants showed decreased collagen deposition after 7 days. Unmodified and aprotinin implants could not be located by 14 days, while 2 of 8 FXIII implants were found, but were significantly degraded. Constructs supported seeded cell survival and organization in vitro, promoting EClined lumen structure formation in construct channels and colocalization of viable ECs and cardiomyocytes. In addition, constructs promoted extracellular matrix deposition by seeded cells, as shown by collagen staining within construct channels and by significant increases in construct stiffness over 10 days in vitro (209% -32%, p < 0.05). The data suggest our fibrin scaffolds are ideally designed to promote graft cell survival and organization, thus improving chances of promoting construct integration with the host tissue upon implantation.

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