Transplantation of Human Embryonic Stem Cell-Derived Cardiomyocytes Improves Myocardial Performance in Infarcted Rat Hearts

Caspi, Oren; Huber, Irit; Kehat, Izhak; Habib, Manhal; Arbel, Gil; Gepstein, Amira; Yankelson, Lior; Aronson, Doron; Beyar, Rafael; Gepstein, Lior

doi:10.1016/j.jacc.2007.07.054

Cited by 508 publications

(386 citation statements)

References 27 publications

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“…(13) Recent publications have demonstrated the development of clinically suitable ex vivo differentiation protocols for obtaining insulin-producing b cells (14,15) and neuronal cells (16,17) from hESCs. Several protocols have been reported in which hESCs were directed to differentiate into musculoskeletal tissue: osteoblastic cells, (18)(19)(20)(21)(22) chondroyctic cells, (23) cardiomyocytes, (24)(25)(26)(27)(28) and skeletal myoblasts. (29) However, most of these protocols relied on using coculture with differentiated cells or complex culture conditions to induce differentiation.…”

Section: Introductionmentioning

confidence: 99%

Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-β/activin/nodal signaling using SB-431542

Mahmood

Harkness²,

Schrøder

et al. 2010

Journal of Bone and Mineral Research

112

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Directing differentiation of human embryonic stem cells (hESCs) into specific cell types using an easy and reproducible protocol is a prerequisite for the clinical use of hESCs in regenerative-medicine procedures. Here, we report a protocol for directing the differentiation of hESCs into mesenchymal progenitor cells. We demonstrate that inhibition of transforming growth factor b (TGF-b)/activin/nodal signaling during embryoid body (EB) formation using SB-431542 (SB) in serum-free medium markedly upregulated paraxial mesodermal markers (TBX6, TBX5) and several myogenic developmental markers, including early myogenic transcriptional factors (Myf5, Pax7), as well as myocyte-committed markers [NCAM, CD34, desmin, MHC (fast), a-smooth muscle actin, Nkx2.5, cTNT]. Continuous inhibition of TGF-b signaling in EB outgrowth cultures (SB-OG) enriched for myocyte progenitor cells; markers were PAX7 þ (25%), MYOD1 þ (52%), and NCAM þ (CD56) (73%). DNA microarray analysis revealed differential upregulation of 117 genes (>2-fold compared with control cells) annotated to myogenic development and function. Moreover, these cells showed the ability to contract (80% of the population) and formed myofibers when implanted intramuscularly in vivo. Interestingly, SB-OG cells cultured in 10% fetal bovine serum (FBS) developed into a homogeneous population of mesenchymal progenitors that expressed CD markers characteristic of mesenchymal stem cells (MSCs): CD44 þ (100%), CD73 þ (98%), CD146 þ (96%), and CD166 þ (88%) with the ability to differentiate into osteoblasts, adipocytes, and chondrocytes in vitro and in vivo. Furthermore, microarray analysis of these cells revealed downregulation of genes related to myogenesis: MYH3 (À167.9-fold), ACTA1 (À161-fold), MYBPH (À139-fold), ACTC (À100.3-fold), MYH8 (À45.5-fold), and MYOT (À41.8-fold) and marked upregulation of genes related to mesoderm-derived cell lineages. In conclusion, our data provides a simple and versatile protocol for directing the differentiation of hESCs into a myogenic lineage and then further into mesenchymal progenitors by blocking the TGF-b signaling pathway. ß

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Section: Introductionmentioning

confidence: 99%

Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-β/activin/nodal signaling using SB-431542

Mahmood

Harkness²,

Schrøder

et al. 2010

Journal of Bone and Mineral Research

112

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“…New human myocardium has been formed recently in infarcted rodent hearts after injection of human embryonic stem cell (hESC)-derived cardiomyocytes, but small graft size and cell death currently limit the benefit of this therapy (1)(2)(3). Delivery of cells in tissue-like structures that preserve cellular attachments could increase cell delivery efficiency and reduce cell death (4).…”

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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.

380

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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“…Due to differences between human and mouse ESC-cardiac myocytes, it is a real challenge to achieve the same high yields of hESC-cardiac myocytes, as can be obtained from the more extensively characterized mouse ESC-cardiac myocytes and more work is needed to define the optimal culture conditions for hESC-cardiac myocytes to maximize the yield. However, some encouraging results have recently been described by Caspi et al (2007). In addition, effective application of hESC-cardiac myocytes requires more defined and reproducible strategies aimed at the development of an efficient cardiac myocyte differentiation system, such as a more straightforward differentiation process.…”

mentioning

confidence: 99%

Deciphering the β‐adrenergic response in human embryonic stem cell‐derived‐cardiac myocytes: closer to clinical use?

Catalucci

Bang

Condorelli

2008

British J Pharmacology

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Human embryonic stem cells (hESCs) are a pluripotent cell type considered to have high potential for the treatment of cardiovascular disease by cell replacement therapies. Several groups have shown that hESCs can be differentiated in vitro into cardiac myocytes, which may be used to facilitate tissue regeneration by injection directly into damaged myocardium. However, several hurdles still need to be overcome before these cells can be used in clinical trials. In particular, because transplanted hESC-cardiac myocytes should integrate fully within the damaged heart, these cells must be functionally compatible with the host myocardium. To assess this aspect of hESC-cardiac myocytes, Brito-Martins et al. (2008) in this issue of the BJP, describe the responses of hESC-cardiac myocytes to b-adrenoceptor stimulation, compared to those of myocytes from adult human hearts. Data obtained using specific b-adrenoceptor agonists showed good compatibility of hESC-cardiac myocytes with adult human myocardium in terms of b-adrenoceptor response.

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Transplantation of Human Embryonic Stem Cell-Derived Cardiomyocytes Improves Myocardial Performance in Infarcted Rat Hearts

Abstract: Transplantation of hESC-CMs after extensive myocardial infarction in rats results in the formation of stable cardiomyocyte grafts, attenuation of the remodeling process, and functional benefit. These findings highlight the potential of hESCs for myocardial cell therapy strategies.

Cited by 508 publications

References 27 publications

Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-β/activin/nodal signaling using SB-431542

Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-β/activin/nodal signaling using SB-431542

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

Deciphering the β‐adrenergic response in human embryonic stem cell‐derived‐cardiac myocytes: closer to clinical use?

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