Skip to main content


We’d like to understand how you use our websites in order to improve them. Register your interest.

Current status of induced pluripotent stem cells in cardiac tissue regeneration and engineering


Myocardial infarction (MI) is associated with damage to the myocardium which results in a great loss of functional cardiomyocytes. As one of the most terminally differentiated organs, the endogenous regenerative potentials of adult hearts are extremely limited and insufficient to compensate for the myocardial loss occurring after MI. Consequentially, exogenous regenerative strategies, especially cell replacement therapy, have emerged and attracted increasing more attention in the field of cardiac tissue regeneration. A renewable source of seeding cells is therefore one of the most important subject in the field. Induced pluripotent stem cells (iPSCs), embryonic stem cell (ESC)-like cells that are derived from somatic cells by reprogramming, represent a promising candidate due to their high potentials for self-renewal, proliferation, differentiation and more importantly, they provide an invaluable method of deriving patient-specific pluripotent stem cells. Therefore, iPSC-based cardiac tissue regeneration and engineering has been extensively investigated in recent years. This review will discuss the achievements and current status in this field, including development of iPSC derivation, in vitro strategies for cardiac generation from iPSCs, cardiac application of iPSCs, challenges confronted at present as well as perspective in the future.


Myocardial infarction (MI), an ischemic heart disease that usually leads to great loss of cardiac tissue and even heart failure, is the leading cause of death through the world [1]. After MI, it is impossible for ischemic heart to restore the scarred myocardium because of its limited regenerative capacity [2]. For the late-stage patients with MI, the only choice is heart transplantation, which is constrained by the insufficiency of donor organs [3]. Recent studies suggested that regeneration or repair of ischemic cardiac tissue may be achieved by cell replacement, i.e. transplantation of cells, especially functional cardiomyocytes to repair or replace damaged myocardium.

Seeding cells used in cardiac regeneration must be of multipotency, at least, into cardiac lineage. In addition, a high capacity of self-renewal and proliferation is also required [4]. In the past decades, many cell types have been used for cardiac regeneration, including skeletal myoblast, primary cardiomyocytes, mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs) [59]. In comparison, ESCs have many potential advantages due to the highly proliferating and cardiomyogenic potentials [10]. Various strategies are available to produce sufficient ESC-cardiomyocytes (ESC-CMs) for replacement therapy [1114], however, the further application of ESCs in cardiac tissue engineering is still hampered due to ethical problem, immune response, etc. [10]. In 2006, a breakthrough has been made that ESC-like cells have been derived from somatic cells by ectopic expression of OCT3/4, Sox2, KLF, c-Myc (induced pluripotent stem cell, iPSC) [15]. iPSCs are highly similar to ESCs in biology. Under suitable conditions, iPSCs could long-term propagate in undifferentiated state or differentiate into many other cell types, including functional cardiomyocytes [16, 17]. Furthermore, the derivation of iPSCs avoid the destruction of embryos and enabled the possibility to obtain patient-specific pluripotent stem cells, providing a promising resolution for clinical immune responses in cell transplantation [18]. Therefore, the development of cell reprogramming or iPSC technology may open up a new perspective to the quickly progressing field of cell-based therapy.

Establishment of iPS cells by cell reprogramming and their implication for regenerative medicine

Development of cell reprogramming

The concept of induced pluripotency was not innovatory. Some other strategies to induce pluripotency have been long developed, such as somatic cell nuclear transfer(SCNT), fusion of somatic cells with ESCs [19].

The pioneering work of directly reprogramming somatic cells into ESC-like state was done by Takahashi and Yamanaka [15]. They applied 4 factors, Sox2, Oct4, and KLF4, c-Myc (termed Yamanaka’s factors later), out of the screened 24 candidate genes to induce pluripotency from mouse embryonic or adult fibroblast; the resulted cells demonstrated a high similarity in morphology, self-renewal and multipotency to ESCs. When performed blastocyst microinjection, these cells formed chimeric embryos. However, the study failed to obtain live chimeric mice with the iPSC line. Closely behind, another independent group in America also successfully derived mouse iPSCs with the same set of factors and further, they obtained live chimeric mice [20]. In the same year, human iPSCs were also successfully established [21].

The development of direct reprogramming was a milestone in stem cell research. It provided an invaluable seeding cell resource for regenerative medicine and tissue engineering. Therefore, since the first derivation of iPSCs was reported, the cells have attracted extensive attention throughout the world. Though most investigators initially followed to use Yamanaka’ factors, it was soon shown that not all of the 4 factors were collectively necessary. For example, NANOG and LIN28 were demonstrated to be able to replace c-MYC and KLF4, Sox1 and Sox3 can replace Sox2 [22]. Further, different group demonstrated that omission of one or more of the 4 factors in some conditions was still sufficient to reprogram somatic cells into iPSCs [23, 24].

Different from SCNT, direct reprogramming strategy (iPSC strategy) is more easy to apply across the species. In the former development, it has been difficult to establish NT-ESC lines in some species. For instance, efforts in establishing rat NT-ESCs were not successful constantly until decade years after the strategy development, while no human NT-ESC line has been established yet. However, the iPSC strategy was extended rapidly across species since the initial derivation of mouse iPSCs. In less than 5 years, iPSCs were successfully derived in many other species, including rhesus, pig, rat, canine, rabbit, Sheep; bovine (Table 1). The cell origins for iPSC derivation were also extended to a range of other cell types (besides fibroblasts), including pancreatic beta cells, lymphocytes, liver, stomach, beta cells, neural progenitor cells, keratinocytes, adipose stem cells, blood, hematopoietic cell, melanocytes, cord blood cells, dental tissues, circulating T cells, endothelial cells, renal tubular cells, ect (Table 1).

Table 1 Development of cell reprograming

The initial development of direct cell reprogramming is based on integrating viral vectors which integrate randomly into the host genome. Risks exist for reactivation of the viral transgenes, such as c-Myc, an oncogene whose reactivation will result in tumor formation [15]. Moreover, integrated provirus may change the neighboring gene expression of receipts. In 2003, Hacein-Bey-Abina and his colleagues have already observed oncogenesis in SCID children who had received the transplantation of retroviral gene-modified haematopoietic stem cells [59]. Therefore, investigators put great efforts on exploring safer vectors to make iPSC more therapeutically applicable. In these years, many other reprogramming vectors and methods were appearing, mainly divided into (i) virus [33], (ii) DNA [57], (iii) RNA [58], and (iv) protein [52]. Some researchers established transgene excision system to generate iPSCs, such as the Cre/LoxP recombination system [60], the moth piggyback transposon system [53]. In these systems, the integrated extraneous genes would be excised after transduction of target cells. Zhou et al. successfully developed a DNA-free strategy to generate iPSCs in which recombinant proteins were used instead of the transcription factors [52]. Though the reprogramming efficiency is rather low (about 1000-fold lower than that of retroviral system), it’s definitely an important advance in that gene transfer is dispensed. In the most recently, RNA was also successfully applied to generate iPSCs [58].

IPSC implication for regenerative medicine

The rapidly progressing field of iPSCs demonstrated vast implications in regenerative medicine and tissue engineering. The high similarity of iPSC to ESC make it a potential replacement of ESCs in therapeutic use, and many advantages make it superior to ESCs:1) the derivation of iPSCs bypass the ethical controversy surrounding ESCs whose derivation get involved in destruction of human embryos; 2) the direct reprogramming somatic cells into ESC-like state enable the possibility to obtain patient-specific stem cells of highly pluripotency, providing a promising perspective to minimizing the immune rejection in cell replacement therapy. Additionally, it needs not to perform invasive procedures to obtain candidate cell because of the extensity of cell types suitable for direct reprogramming; 3) to obtain autologous normal cells from patients of genetic diseases. Fanconi anaemia is a disease of severe genetic instability. Fibroblasts or keratinocytes derived from the patients carry severe genetic defects which do not allow patient-specific iPS cell generation. However, the genetic defect can be corrected with lentiviral vectors encoding FANCA or FANCD2 and corrected fibroblasts could be induced into iPS cells as efficiently as wild-type human fibroblasts. These iPS cells have equal capability as normal ones to differentiate into haematopoietic progenitors, whilst stably maintaining the disease-free phenotype in vitro [61]. The similar situation also exists in many other genetic hiPS cells. The derivation of autologous disease-free cells from these genetic-defect patient possess great therapeutic value when cell transplantation is needed.

To date, though developed for only several years, the great value of iPSCs in regenerative medicine and tissue engineering has been definitely displayed at least in the following aspects:

  1. 1)

    Be used as seeding cells for cell transplantation therapy. A typical instance of iPSC therapeutic application was Hanna J and his colleagues’ work. They demonstrated the feasibility to correct the defect by coupling gene targeting and direct reprogramming using a mouse model of humanized sickle cell anemia [62]. Similarly, Wernig and colleagues showed that iPS-cell-derived dopaminergic neurons could alleviate the disease phenotype in a rat model of Parkinson’s disease [63]. In addition, it has been confirmed too that iPSC treatment was effective for cardiovascular disease, spinal cord injury and many other diseases [6467];

  2. 2)

    Be used for human disease models. Disease-specific iPSCs and their derivates would exhibit at least partial phenotype of the disease. One typical example is that iPSCs derivated from patients with heart disease differentiated into cardiomyocytes which would exhibit the specific disease behavior, such as long QT syndrome, Timothy syndrome, and LEAPORD syndrome [6870]. Such disease-specific cells would be convenient and valuable in experimental research (such as pathogenesis, physiologic properties of these cardiomyocytes) because it is nearly impossible to obtain abundant samples from the patients. At present, several disease-specific iPSC line have already been established, including juvenile onset type 1 diabetes mellitus, Parkinson’s disease [71], amyitrophic lateral sclerosis [72], spinal muscular atrophy (SMA) [73];

  3. 3)

    Be used for high throughout drug screen. iPSCs could differentiated into many type of functional lineage-specific cells, which could be used for drug screening, drug effectiveness and toxicology tests instead of natural tissue. In the following part of the review, we will focus on the current status of iPSC’s application in cardiac tissue regeneration and engineering.

In vitro strategies for cardiac generation from iPS cells

Of all stem cells potentially applicable in cardiac tissue engineering, ESC represents one of the most promising cell sources. ESCs possess potent capacities of long term expansion and efficiently cardiomyogenic differentiation, which allows for the creation of sufficient cardiomyocytes or supportive cardiac-lineage cells, such as vascular progenitor cells, smooth muscle cells and endothelial cells [1]. As ESC-like state cells, the advantages of ESCs in cardiac regeneration are manifested in iPSCs too.

The differentiation of iPSCs into cardiomyocytes in vitro was firstly reported in mouse iPSC lines by Christina and colleagues in 2008 [16]. The resulted cardiomyocytes showed typical features of ES cell–derived cardiomyocytes, including spontaneous rhythmical beating, expression of marker genes, expression of cardiomyocyte-typical proteins, spontaneous rhythmic intracellular Ca2+ fluctuations, presence of the β-adrenergic and muscarinic signaling cascade, and so on. But in the study, iPSCs showed a delayed and less efficient differentiation of beating EBs compared with ESCs. Almost at the same time, Genta et al. reported the direct and systematic differentiation of miPSCs into cardiac lineages [74]. MiPSCs were firstly induced into Flk1+ cells and sorted by FACS, then purified Flk1+ were systematically differentiated into endothelial cells, mural cells, arterial/venous/lymphatic endothelial cells and self-beating cardiomyocytes in different conditions, respectively. Different from Christina’s report, the differentiation properties of iPSCs observed in the study were almost the same to that of ES cells. Followed in 2009, Jianhua Zhang et al. firstly reported the cardiac differentiation of human iPSCs [17]. In the study, differentiation properities were also compared between hiPSCs and hESCs. The study showed that both hiPSCs and hESCs have a similar capacity for differentiation into nodal-, atrial-, and ventricular-like phenotypes as analysized by electrophysiology. HiPS and hES cell-derived cardiomyocytes share similar cardiac gene expression patterns, proliferation, sarcomeric organizations and they exhibited similar responsive pattern to β-adrenergic stimulation. However, the study observed a similar phenomenon as observed in miPSCs, that the differentiation efficiencies of hiPSCs varied with cell lines. These studies (both on mouse and human iPSC lines) coincidentally indicated that cardiomyogenic potentials of iPSCs could be line-specific.

In recent years, many other methods for differentiating iPSCs into cardiomyocytes have been developed (Table 2). Theoretically, any strategies and reagents differentiated ESCs into cardiac lineage may be applied to iPSCs due to their highly similarity. Actually, many methods used for iPSC cardiac differentiation are based on the previous studies in ESCs. BMP4 and activin A are potent factors that induced hESCs into cardiomyocytes [14]. Therefore, both of them are definitely candidate inducers to differentiate hiPSC into cardiomyocytes. In a direct differentiation system reported by Hideki Uosaki et al., BMP4, activin A and bFGF were combined to induced iPSCs differentiation [75], the induced cardiomyocytes (cardiac troponin-T –positive) appeared robustly with 30–70% efficiency. In a EB-based differentiation sysytem reported by Paul W. Burridge, et al. [76], they combined BMP4, FGF2, polyvinyl alcohol, serum, and insulin to induced cardiac differentiation from hiPSCs and hESCs. At optimized concentrations, the differentiated rates of contracting EBs were enhanced up to more than 90%. Further, in the contracting hEBs, 64–89% of cells were cardiomyocytes. Many other inducers used in cardiac differentiation of ESCs were also confirmed effective to induced cardiac differentiation from iPSCs, including, 5-Azacytidine, ascorbic acid, cyclosporine-A and so on (Table 2). Of note, though the differentiation efficiencies varied among these methods, it is difficult to determine which one is absolutely superior without the direct comparison between different methods on the same cell line, because the differentiation of iPSCs toward cardiomyocytes may be cell-line-dependent as discussed above. Interestingly, in another report by Shinji Kaichi, et al., investigators explored trichostatin A to improve iPSCs’ cardiac differentiation and found that treating iPSCs with trichostatin A seems to be useful to overcome cell line variation in the differentiation efficiency [77]. The reagent only or combined with other inducers may be promising in future application to facilitate cardiac differentiation of different iPSC lines, especially those could not be substituted, e.g., patient-specific iPSCs. Recently, Lee Carpenter et al. reported an efficient method for iPSCs differentiation into cardiac lineages [78]. In the study, iPSCs were differentiated as a monolayer. By combining PenStrep, monothioglycerol, ascorbic acid and several cytokines (including active A, BMP4 and bFGF), the method yielded more 50% cardiac-lineage cells (cardiomyocytes, endothelium or smooth muscle cells) out of total differentiated cells. Though the method is some complex and many inducers are involved, such a high efficiency for cardiac cell derivation from iPSCs would be clinically promising.

Table 2 Cardiac differentiation from iPSCs

Current application of iPSC in cardiac tissue regeneration and engineering

The application of ESCs in cardiac tissue regeneration and engineering could be tracked back to 2002. Min JY et al. firstly injected ESCs in a MI rat model [91], and found that ESCs survived and regenerated cardiomyocytes in recipient myocardium and significantly improved heart function 6 weeks after cell transplantation. The study demonstrated the feasibility and validity of applying ESCs for myocardial repair and regeneration. Thereafter, the researches about ESC application in cardiac tissue regeneration and engineering grew rapidly. Many novel strategies emerged besides the direct transplantation of ESCs to optimize the therapeutic efficiency, such as injectable cardiac tissue engineering [9] (delivering ESCs in injectable biomaterials), pre-treatment of ESCs before transplantation [92], genetic modification [93], engineered cardiac tissue [94] and so on. Many ESC-derivated cells besides undifferentiated ESCs were explored to determine the optimal cell types, such as ESC-derived cardiomyocytes [11], ESC-derived endothelial cells [95], ESC-derived endothelial progenitors [96], ESC-derived pluripotent cells [97], and so on. Like the in vitro studies, the in vivo application of iPSCs in cardiac tissue regeneration and engineering also adopt a similar route as that of ESCs. However, as a newly emerging field, iPSC-based cardiac tissue regeneration and engineering is still preliminary.

The pioneer work that translates the concept of notion into practice was reported in 2009 by Timothy J. Nelson and his colleagues [64]. Within adult murine models of myocardial infarction, undifferentiated iPSCs were intramyocardial delivered by needle injection. Engrafted iPSCs restored myocardial performance, halted progression of pathologic remodeling in infarcted hearts and regenerated multi-lineage cardiac tissue, including cardiomyocytes (cardiac α-actinin positive), smooth muscle cells (Smooth muscle α-actin positive) and endothelial cells (CD31 positive). However, the observation in the study that iPSCs did not form detectable tumors in immunocompetent recipient hearts was soon disputed in subsequent reports [98, 99]. To minimize tumorigenic risk and optimize therapeutic efficiency of iPSCs for myocardial repair, Christina Mauritz and colleagues explored the usage of iPSC derived Flk+ cardiovascular progenitor cells in mouse model56. The data presented in the study demonstrated an encouraging efficiency of iPSC-derived cardiovascular progenitors for myocardial regeneration, but the tracking time in the study was rather short, only 2 weeks. Whether and how long the therapeutic benefits, as well as the survival of grafts could be maintained are unknown and deserve further investigation. Besides application in small animals, the therapeutic potential of human iPSCs for myocardial repair was also tested in higher animals (clinically more relevant animal models) [100]. Christian Templin et al. injected human iPSCs in pig models of MI and found that human iPSCs could be detected for up to 15w in pig myocardium. More importantly, they observed hiPSC-derived endothelial cells contributed to vascularization of infarcted myocardium.

Delivery method is a key factor that may influences the success of cell-based therapy.

From studies described above, though delivering iPSC with needle injection has acquired significant efficacy for myocardial repair, the limited cell number that could be delivered or detained in the target region is an apparent disadvantage for injection approach. Therefore, more effective method for delivering iPSCs was also developed.

Innovative from precious studies based on needle injection, Bo Dai and colleagues explore an tissue engineering strategy to create a tri-cell patch using iPSC-derived cardiomyocytes, endothelial cells and embryonic fibroblasts for myocardial repair in mice, resulting in significantly more cell survival, enhanced left ventricle (LV) function and reduced LV fibrosis. By present, this appears to be the most successful application of iPSCs in cardiac tissue engineering [101, 102].

Overall, though the in vitro strategies on the generation of cardiomyocytes from iPSCs are rapidly progressing, the in vivo application of iPSCs in cardiac tissue regeneration and engineering is still in infancy. Comparison between in vitro and in vivo studies may indicate that researchers are more cautious about in vivo application of iPSCs. To promote the future therapeutic application of iPSCs, more effective strategies for cell delivery need developing, novel means to enhance the survival, engraft and therapeutic efficiency of transplanted cells should be explored, the long-term validation and safety after iPSCs transplantation as well as the optimized cell population need to be determined.

Current challenges confronted in iPSC-based cardiac tissue regeneration and engineering

Although many studies available supported that iPSCs could be a potential substitution of ESCs and represent a promising cell sources for cardiac tissue regeneration, lots of challenges remain and must be overcome prior their clinical applications.

  1. 1)

    Reprogramming efficiency is still low and reprogramming mechanisms are not exactly elicited. These years, though reprogramming technologies progressed at a high-speed pace and various strategies or augmented reagents appeared, the virus-mediated reprogramming still seems to be the most effective way. In addition, the derivation of iPSCs is not repetitive. The number of insertions of exogenous genes, the locus of gene insertion as well as the extent of reprogramming could vary among each reprogramming, even though the original cells were the same. One direct consequence in therapeutic use may be that one iPSC line is effective in myocardial regeneration and repair but another not. Actually, it has been founded that the pluripotency, including cardiomyogenic potential differs greatly among iPSC lines [77]. The resolution of the problems will largely depend on the better understanding of the reprogramming mechanisms.

  2. 2)

    Common to ESCs, the tumorigenicity is also an obstacle preventing the further application of iPSCs. Recently, two independent studies in mice and rats consistently indicated that intramyocardial transplantation of iPSCs is accompanied with a high tumorigenic risk [98, 99]. Furthermore, it seems that iPSCs derived progenies retain tumorigenic potential too [103]. Some investigators have tried to obviate the tumorigenic capacity of iPSCs reprogramming, such as excluding c-Myc in reprogramming [32]. Unfortunately, they do not work well in deed.

  3. 3)

    A practical strategy for iPSC differentiation and target cell purification is needed. The differentiation rates of iPSCs into cardiac-lineage cells varied among strategies and cell lines, but generally, not a single report is ideal to meet clinical standard. Additionally, an effective and practical method for target cell selection is desired as adverse cells could long term exist during iPSC differentiation and may result in unpredicted side effects after in vivo transplantation [103].

  4. 4)

    The immunogenicity of iPSCs should be considered renewedly. Given that iPS cells can be derived from patients themselves, it had been considered that iPSCs provided a possibility to overcome problems of immunological rejection associated with cell transplantation. However, a latest report by Zhao et el. showed that iPSCs may possess a higher immunogenicity than predicted and evoked immune response even in syngeneic recipient [104]. Some mechanisms for increased immunogenicity in iPSCs were proposed too by the study, such as abnormal overexpression of some genes. Accordingly, an effective strategy to control immunogenicity of iPSCs in reprogramming is indispensable on their way to clinical practice, and each iPSC line need to be strictly examined before transplantation, including patient-specific iPSCs.

In addition, there are also several fundamental challenges common to iPSCs and other cells in cardiac application, e.g., it has been reported that ESC-CMs possessed a low capacity for electrophysiological integration [105]; which could be an obstacle too for iPSC-based myocardial repair. Other challenges include poor retention and survival of transplanted cells in target regions, long-term efficacy, arrhythogenic risk, and so on.

Perspective and conclusion

Just within six years, the experimental achievements in iPSC research have generated great expectations in both clinicians and patients. At present, the iPSCs have been beginning contributing to the treatment of cardiovascular and other diseases. On one hand, the disease models established from iPSCs have been confirmed effective and used for research of physiologic properties, pathogenesis of some diseases, including heart disease (e.g. Timothy syndrome), nervous system diseases(e.g. Parkinson’s disease) and many other genetic diseases. On the other hand, iPSCs have already been used in the drug screening for disease treatment [106, 107]. Despite these progresses, the therapeutic application of iPSCs for MI is still at an early stage (limited in animal models), no clinical application of iPSCs has come true. Thus, more effects are still needed to derive clinical-grade iPSC lines and overcome so many challenges.


In summary, the iPSC research has been progressing with an amazing speed from the first onset, encouraging achievements have been unceasingly emerging and all these are just the start. Current problems referring to iPSC application in cardiac regeneration as well as in other areas of regenerative medicine should be looked with optimism. The scientific community is sparing no effort to push the advancements in iPSC basic research and its clinical use. Several novel techniques have also demonstrated promising perspectives related to the resolution of relative problems, such as novel chemicals/compounds or systems to enhanced reprogramming efficiency [108]; novel reprogramming notion to avoid tumorigenicity [109, 110]. Meanwhile, it should be objectively looked that each small step toward clinic would depend on the tremendous efforts in basic research. Despite the remarkable achievements in iPSC research within such a short time, it should be said that there is still a long way to go and many barriers to overcome before the true realization of iPSC application in clinical practice.



Myocardial infarction


Induced pluripotent stem cell


Embryonic stem cell


Embryoid body




Familial dysautonomia


Somatic cell nuclear transfer


Spinal muscular atrophy


Fluorescence-activated cell sorting


Left ventricle


Vitamin C.


  1. 1.

    Segers VF, Lee RT: Stem-cell therapy for cardiac disease. Nature 2008, 451: 937–942. 10.1038/nature06800

  2. 2.

    Zimmermann WH, Melnychenko I, Wasmeier G, Didie M, Naito H, Nixdorff U, Hess A, Budinsky L, Brune K, Michaelis B, Dhein S, Schwoerer A, Ehmke H, Eschenhagen T: Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med 2006, 12: 452–458. 10.1038/nm1394

  3. 3.

    Patel J, Kobashigawa JA: Cardiac transplantation: the alternate list and expansion of the donor pool. Curr Opin Cardiol 2004, 19: 162–165. 10.1097/00001573-200403000-00017

  4. 4.

    Wang H, Zhou J, Liu Z, Wang C: Injectable cardiac tissue engineering for the treatment of myocardial infarction. J Cell Mol Med 2010, 14: 1044–1055.

  5. 5.

    Hahn JY, Cho HJ, Kang HJ, Kim TS, Kim MH, Chung JH, Bae JW, Oh BH, Park YB, Kim HS: Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. J Am Coll Cardiol 2008, 51: 933–943. 10.1016/j.jacc.2007.11.040

  6. 6.

    Christman KL, Vardanian AJ, Fang Q, Sievers RE, Fok HH, Lee RJ: Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J Am Coll Cardiol 2004, 44: 654–660. 10.1016/j.jacc.2004.04.040

  7. 7.

    Gao LR, Wang ZG, Zhang NK, He S, Yao L, Ning HY, Kang XL, Fei YX, Zhu ZM, Yang Y: Transplantation of fetal cardiomyocyte regenerates infarcted myocardium in rats. Zhonghua Yi Xue Za Zhi 2003, 83: 1818–1822.

  8. 8.

    Kofidis T, Lebl DR, Martinez EC, Hoyt G, Tanaka M, Robbins RC: Novel injectable bioartificial tissue facilitates targeted, less invasive, large-scale tissue restoration on the beating heart after myocardial injury. Circulation 2005, 112: I173-I177.

  9. 9.

    Lu WN, Lu SH, Wang HB, Li DX, Duan CM, Liu ZQ, Hao T, He WJ, Xu B, Fu Q, Song YC, Xie XH, Wang CY: Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Eng Part A 2009, 15: 1437–1447. 10.1089/ten.tea.2008.0143

  10. 10.

    Passier R, van Laake LW, Mummery CL: Stem-cell-based therapy and lessons from the heart. Nature 2008, 453: 322–329. 10.1038/nature07040

  11. 11.

    Kolossov E, Bostani T, Roell W, Breitbach M, Pillekamp F, Nygren JM, Sasse P, Rubenchik O, Fries JW, Wenzel D, Geisen C, Xia Y, Lu Z, Duan Y, Kettenhofen R, Jovinge S, Bloch W, Bohlen H, Welz A, Hescheler J, Jacobsen SE, Fleischmann BK: Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med 2006, 203: 2315–2327. 10.1084/jem.20061469

  12. 12.

    Takahashi T, Lord B, Schulze PC, Fryer RM, Sarang SS, Gullans SR, Lee RT: Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 2003, 107: 1912–1916. 10.1161/01.CIR.0000064899.53876.A3

  13. 13.

    Caspi O, Huber I, Kehat I, Habib M, Arbel G, Gepstein A, Yankelson L, Aronson D, Beyar R, Gepstein L: Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts. J Am Coll Cardiol 2007, 50: 1884–1893. 10.1016/j.jacc.2007.07.054

  14. 14.

    Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, Reinecke H, Xu C, Hassanipour M, Police S, O’Sullivan C, Collins L, Chen Y, Minami E, Gill EA, Ueno S, Yuan C, Gold J, Murry CE: Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 2007, 25: 1015–1024. 10.1038/nbt1327

  15. 15.

    Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126: 663–676. 10.1016/j.cell.2006.07.024

  16. 16.

    Mauritz C, Schwanke K, Reppel M, Neef S, Katsirntaki K, Maier LS, Nguemo F, Menke S, Haustein M, Hescheler J, Hasenfuss G, Martin U: Generation of functional murine cardiac myocytes from induced pluripotent stem cells. Circulation 2008, 118: 507–517. 10.1161/CIRCULATIONAHA.108.778795

  17. 17.

    Zhang J, Wilson GF, Soerens AG, Koonce CH, Yu J, Palecek SP, Thomson JA, Kamp TJ: Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 2009, 104: e30-e41. 10.1161/CIRCRESAHA.108.192237

  18. 18.

    Asgari S, Pournasr B, Salekdeh GH, Ghodsizadeh A, Ott M, Baharvand H: Induced pluripotent stem cells: a new era for hepatology. J Hepatol 2010, 53: 738–751. 10.1016/j.jhep.2010.05.009

  19. 19.

    Patel M, Yang S: Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem Cell Rev 2010, 6: 367–380. 10.1007/s12015-010-9123-8

  20. 20.

    Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R: In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007, 448: 318–324. 10.1038/nature05944

  21. 21.

    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131: 861–872. 10.1016/j.cell.2007.11.019

  22. 22.

    Maherali N, Hochedlinger K: Guidelines and techniques for the generation of induced pluripotent stem cells. Cell Stem Cell 2008, 3: 595–605. 10.1016/j.stem.2008.11.008

  23. 23.

    Zhao HX, Li Y, Jin HF, Xie L, Liu C, Jiang F, Luo YN, Yin GW, Wang J, Li LS, Yao YQ, Wang XH: Rapid and efficient reprogramming of human amnion-derived cells into pluripotency by three factors OCT4/SOX2/NANOG. Differentiation 2010, 80: 123–129. 10.1016/j.diff.2010.03.002

  24. 24.

    Giorgetti A, Montserrat N, Rodriguez-Piza I, Azqueta C, Veiga A, Izpisua Belmonte JC: Generation of induced pluripotent stem cells from human cord blood cells with only two factors: Oct4 and Sox2. Nat Protoc 2010, 5: 811–820. 10.1038/nprot.2010.16

  25. 25.

    Liu H, Zhu F, Yong J, Zhang P, Hou P, Li H, Jiang W, Cai J, Liu M, Cui K, Qu X, Xiang T, Lu D, Chi X, Gao G, Ji W, Ding M, Deng H: Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 2008, 3: 587–590. 10.1016/j.stem.2008.10.014

  26. 26.

    Ezashi T, Telugu BP, Alexenko AP, Sachdev S, Sinha S, Roberts RM: Derivation of induced pluripotent stem cells from pig somatic cells. Proc Natl Acad Sci USA 2009, 106: 10993–10998. 10.1073/pnas.0905284106

  27. 27.

    Li W, Wei W, Zhu S, Zhu J, Shi Y, Lin T, Hao E, Hayek A, Deng H, Ding S: Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 2009, 4: 16–19. 10.1016/j.stem.2008.11.014

  28. 28.

    Shimada H, Nakada A, Hashimoto Y, Shigeno K, Shionoya Y, Nakamura T: Generation of canine induced pluripotent stem cells by retroviral transduction and chemical inhibitors. Mol Reprod Dev 2010, 77: 2.

  29. 29.

    Honda A, Hirose M, Hatori M, Matoba S, Miyoshi H, Inoue K, Ogura A: Generation of induced pluripotent stem cells in rabbits: potential experimental models for human regenerative medicine. J Biol Chem 2010, 285: 31362–31369. 10.1074/jbc.M110.150540

  30. 30.

    Li Y, Cang M, Lee AS, Zhang K, Liu D: Reprogramming of sheep fibroblasts into pluripotency under a drug-inducible expression of mouse-derived defined factors. PLoS ONE 2011, 6: e15947. 10.1371/journal.pone.0015947

  31. 31.

    Huang B, Li T, Alonso-Gonzalez L, Gorre R, Keatley S, Green A, Turner P, Kallingappa PK, Verma V, Oback B: A virus-free poly-promoter vector induces pluripotency in quiescent bovine cells under chemically defined conditions of dual kinase inhibition. PLoS ONE 2011, 6: e24501. 10.1371/journal.pone.0024501

  32. 32.

    Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S: Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008, 26: 101–106. 10.1038/nbt1374

  33. 33.

    Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, Clark AT, Plath K: Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA 2008, 105: 2883–2888. 10.1073/pnas.0711983105

  34. 34.

    Stadtfeld M, Brennand K, Hochedlinger K: Reprogramming of pancreatic beta cells into induced pluripotent stem cells. Curr Biol 2008, 18: 890–894. 10.1016/j.cub.2008.05.010

  35. 35.

    Eminli S, Utikal J, Arnold K, Jaenisch R, Hochedlinger K: Reprogramming of neural progenitor cells into induced pluripotent stem cells in the absence of exogenous Sox2 expression. Stem Cells 2008, 26: 2467–2474. 10.1634/stemcells.2008-0317

  36. 36.

    Aasen T, Raya A, Barrero MJ, Garreta E, Consiglio A, Gonzalez F, Vassena R, Bilic J, Pekarik V, Tiscornia G, Edel M, Boue S, Izpisua Belmonte JC: Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 2008, 26: 1276–1284. 10.1038/nbt.1503

  37. 37.

    Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K: Induced pluripotent stem cells generated without viral integration. Science 2008, 322: 945–949. 10.1126/science.1162494

  38. 38.

    Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, Yamanaka S: Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science 2008, 321: 699–702. 10.1126/science.1154884

  39. 39.

    Sun N, Panetta NJ, Gupta DM, Wilson KD, Lee A, Jia F, Hu S, Cherry AM, Robbins RC, Longaker MT, Wu JC: Feeder-free derivation of induced pluripotent stem cells from adult human adipose stem cells. Proc Natl Acad Sci USA 2009, 106: 15720–15725. 10.1073/pnas.0908450106

  40. 40.

    Loh YH, Agarwal S, Park IH, Urbach A, Huo H, Heffner GC, Kim K, Miller JD, Ng K, Daley GQ: Generation of induced pluripotent stem cells from human blood. Blood 2009, 113: 5476–5479. 10.1182/blood-2009-02-204800

  41. 41.

    Okabe M, Otsu M, Ahn DH, Kobayashi T, Morita Y, Wakiyama Y, Onodera M, Eto K, Ema H, Nakauchi H: Definitive proof for direct reprogramming of hematopoietic cells to pluripotency. Blood 2009, 114: 1764–1767. 10.1182/blood-2009-02-203695

  42. 42.

    Utikal J, Maherali N, Kulalert W, Hochedlinger K: Sox2 is dispensable for the reprogramming of melanocytes and melanoma cells into induced pluripotent stem cells. J Cell Sci 2009, 122: 3502–3510. 10.1242/jcs.054783

  43. 43.

    Giorgetti A, Montserrat N, Aasen T, Gonzalez F, Rodriguez-Piza I, Vassena R, Raya A, Boue S, Barrero MJ, Corbella BA, Torrabadella M, Veiga A, Izpisua Belmonte JC: Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 2009, 5: 353–357.

  44. 44.

    Yan X, Qin H, Qu C, Tuan RS, Shi S, Huang GT: iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin. Stem Cells Dev 2010, 19: 469–480. 10.1089/scd.2009.0314

  45. 45.

    Seki T, Yuasa S, Oda M, Egashira T, Yae K, Kusumoto D, Nakata H, Tohyama S, Hashimoto H, Kodaira M, Okada Y, Seimiya H, Fusaki N, Hasegawa M, Fukuda K: Generation of induced pluripotent stem cells from human terminally differentiated circulating T cells. Cell Stem Cell 2010, 7: 11–14. 10.1016/j.stem.2010.06.003

  46. 46.

    Panopoulos AD, Ruiz S, Yi F, Herrerias A, Batchelder EM, Izpisua Belmonte JC: Rapid and highly efficient generation of induced pluripotent stem cells from human umbilical vein endothelial cells. PLoS ONE 2011, 6: e19743. 10.1371/journal.pone.0019743

  47. 47.

    Zhou T, Benda C, Duzinger S, Huang Y, Li X, Li Y, Guo X, Cao G, Chen S, Hao L, Chan YC, Ng KM, Ho JC, Wieser M, Wu J, Redl H, Tse HF, Grillari J, Grillari-Voglauer R, Pei D, Esteban MA: Generation of induced pluripotent stem cells from urine. J Am Soc Nephrol 2011, 22: 1221–1228. 10.1681/ASN.2011010106

  48. 48.

    Shi Y, Do JT, Desponts C, Hahm HS, Scholer HR, Ding S: A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell 2008, 2: 525–528. 10.1016/j.stem.2008.05.011

  49. 49.

    Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S: Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008, 322: 949–953. 10.1126/science.1164270

  50. 50.

    Fusaki N, Ban H, Nishiyama A, Saeki K, Hasegawa M: Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 2009, 85: 348–362. 10.2183/pjab.85.348

  51. 51.

    Abujarour R, Ding S: Induced pluripotent stem cells free of exogenous reprogramming factors. Genome Biol 2009, 10: 220. 10.1186/gb-2009-10-5-220

  52. 52.

    Zhou H, Wu S, Joo JY, Zhu S, Han DW, Lin T, Trauger S, Bien G, Yao S, Zhu Y, Siuzdak G, Scholer HR, Duan L, Ding S: Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009, 4: 381–384. 10.1016/j.stem.2009.04.005

  53. 53.

    Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hamalainen R, Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung HK, Nagy A: PiggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009, 458: 766–770. 10.1038/nature07863

  54. 54.

    Gonzalez F, Barragan Monasterio M, Tiscornia G, Montserrat Pulido N, Vassena R, Batlle Morera L, Rodriguez Piza I, Izpisua Belmonte JC: Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector. Proc Natl Acad Sci USA 2009, 106: 8918–8922. 10.1073/pnas.0901471106

  55. 55.

    Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R, Kim KS: Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 2009, 4: 472–476. 10.1016/j.stem.2009.05.005

  56. 56.

    Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA: Human induced pluripotent stem cells free of vector and transgene sequences. Science 2009, 324: 797–801. 10.1126/science.1172482

  57. 57.

    Jia F, Wilson KD, Sun N, Gupta DM, Huang M, Li Z, Panetta NJ, Chen ZY, Robbins RC, Kay MA, Longaker MT, Wu JC: A nonviral minicircle vector for deriving human iPS cells. Nat Methods 2010, 7: 197–199. 10.1038/nmeth.1426

  58. 58.

    Li Z, Yang CS, Nakashima K, Rana TM: Small RNA-mediated regulation of iPS cell generation. EMBO J 2011, 30: 823–834. 10.1038/emboj.2011.2

  59. 59.

    Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M: LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003, 302: 415–419. 10.1126/science.1088547

  60. 60.

    Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K: Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009, 458: 771–775. 10.1038/nature07864

  61. 61.

    Raya A, Rodriguez-Piza I, Guenechea G, Vassena R, Navarro S, Barrero MJ, Consiglio A, Castella M, Rio P, Sleep E, Gonzalez F, Tiscornia G, Garreta E, Aasen T, Veiga A, Verma IM, Surralles J, Bueren J, Izpisua Belmonte JC: Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 2009, 460: 53–59. 10.1038/nature08129

  62. 62.

    Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R: Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007, 318: 1920–1923. 10.1126/science.1152092

  63. 63.

    Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R: Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA 2008, 105: 5856–5861. 10.1073/pnas.0801677105

  64. 64.

    Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A: Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation 2009, 120: 408–416. 10.1161/CIRCULATIONAHA.109.865154

  65. 65.

    Fujimoto Y, Abematsu M, Falk A, Tsujimura K, Sanosaka T, Juliandi B, Semi K, Namihira M, Komiya S, Smith A, Nakashima K: Treatment of a mouse model of spinal cord injury by transplantation of human iPS cell-derived long-term self-renewing neuroepithelial-like stem cells. Stem Cells 2012, 30: 1163–1173. 10.1002/stem.1083

  66. 66.

    Oki K, Tatarishvili J, Woods J, Koch P, Wattananit S, Mine Y, Monni E, Prietro DT, Ahlenius H, Ladewig J, Brustle O, Lindvall O, Kokaia Z: Human induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells 2012, 30: 1120–1133. 10.1002/stem.1104

  67. 67.

    Chang HM, Liao YW, Chiang CH, Chen YJ, Lai YH, Chang YL, Chen HL, Jeng SY, Hsieh JH, Peng CH, Li HY, Chien Y, Chen SY, Chen LK, Huo TI: Improvement of carbon tetrachloride-induced acute hepatic failure by transplantation of induced pluripotent stem cells without reprogramming factor c-Myc. Int J Mol Sci 2012, 13: 3598–3617. 10.3390/ijms13033598

  68. 68.

    Malan D, Friedrichs S, Fleischmann BK, Sasse P: Cardiomyocytes obtained from induced pluripotent stem cells with long-QT syndrome 3 recapitulate typical disease-specific features in vitro. Circ Res 2011, 109: 841–847. 10.1161/CIRCRESAHA.111.243139

  69. 69.

    Yazawa M, Hsueh B, Jia X, Pasca AM, Bernstein JA, Hallmayer J, Dolmetsch RE: Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome. Nature 2011, 471: 230–234. 10.1038/nature09855

  70. 70.

    Carvajal-Vergara X, Sevilla A, D’Souza SL, Ang YS, Schaniel C, Lee DF, Yang L, Kaplan AD, Adler ED, Rozov R, Ge Y, Cohen N, Edelmann LJ, Chang B, Waghray A, Su J, Pardo S, Lichtenbelt KD, Tartaglia M, Gelb BD, Lemischka IR: Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 2010, 465: 808–812. 10.1038/nature09005

  71. 71.

    Park IH, Arora N, Huo H, Maherali N, Ahfeldt T, Shimamura A, Lensch MW, Cowan C, Hochedlinger K, Daley GQ: Disease-specific induced pluripotent stem cells. Cell 2008, 134: 877–886. 10.1016/j.cell.2008.07.041

  72. 72.

    Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K: Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 2008, 321: 1218–1221. 10.1126/science.1158799

  73. 73.

    Ebert AD, Yu J, Rose FF Jr, Mattis VB, Lorson CL, Thomson JA, Svendsen CN: Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 2009, 457: 277–280. 10.1038/nature07677

  74. 74.

    Narazaki G, Uosaki H, Teranishi M, Okita K, Kim B, Matsuoka S, Yamanaka S, Yamashita JK: Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. Circulation 2008, 118: 498–506. 10.1161/CIRCULATIONAHA.108.769562

  75. 75.

    Uosaki H, Fukushima H, Takeuchi A, Matsuoka S, Nakatsuji N, Yamanaka S, Yamashita JK: Efficient and scalable purification of cardiomyocytes from human embryonic and induced pluripotent stem cells by VCAM1 surface expression. PLoS ONE 2011, 6: e23657. 10.1371/journal.pone.0023657

  76. 76.

    Burridge PW, Thompson S, Millrod MA, Weinberg S, Yuan X, Peters A, Mahairaki V, Koliatsos VE, Tung L, Zambidis ET: A universal system for highly efficient cardiac differentiation of human induced pluripotent stem cells that eliminates interline variability. PLoS ONE 2011, 6: e18293. 10.1371/journal.pone.0018293

  77. 77.

    Kaichi S, Hasegawa K, Takaya T, Yokoo N, Mima T, Kawamura T, Morimoto T, Ono K, Baba S, Doi H, Yamanaka S, Nakahata T, Heike T: Cell line-dependent differentiation of induced pluripotent stem cells into cardiomyocytes in mice. Cardiovasc Res 2010, 88: 314–323. 10.1093/cvr/cvq189

  78. 78.

    Carpenter L, Carr C, Yang CT, Stuckey DJ, Clarke K, Watt SM: Efficient differentiation of human induced pluripotent stem cells generates cardiac cells that provide protection following myocardial infarction in the rat. Stem Cells Dev 2012, 21: 977–986. 10.1089/scd.2011.0075

  79. 79.

    Yokoo N, Baba S, Kaichi S, Niwa A, Mima T, Doi H, Yamanaka S, Nakahata T, Heike T: The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells. Biochem Biophys Res Commun 2009, 387: 482–488. 10.1016/j.bbrc.2009.07.052

  80. 80.

    Zwi L, Caspi O, Arbel G, Huber I, Gepstein A, Park IH, Gepstein L: Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation 2009, 120: 1513–1523. 10.1161/CIRCULATIONAHA.109.868885

  81. 81.

    Gai H, Leung EL, Costantino PD, Aguila JR, Nguyen DM, Fink LM, Ward DC, Ma Y: Generation and characterization of functional cardiomyocytes using induced pluripotent stem cells derived from human fibroblasts. Cell Biol Int 2009, 33: 1184–1193. 10.1016/j.cellbi.2009.08.008

  82. 82.

    Kuzmenkin A, Liang H, Xu G, Pfannkuche K, Eichhorn H, Fatima A, Luo H, Saric T, Wernig M, Jaenisch R, Hescheler J: Functional characterization of cardiomyocytes derived from murine induced pluripotent stem cells in vitro. FASEB J 2009, 23: 4168–4180. 10.1096/fj.08-128546

  83. 83.

    Moretti A, Bellin M, Jung CB, Thies TM, Takashima Y, Bernshausen A, Schiemann M, Fischer S, Moosmang S, Smith AG, Lam JT, Laugwitz KL: Mouse and human induced pluripotent stem cells as a source for multipotent Isl1+ cardiovascular progenitors. FASEB J 2010, 24: 700–711. 10.1096/fj.09-139477

  84. 84.

    Xi J, Khalil M, Shishechian N, Hannes T, Pfannkuche K, Liang H, Fatima A, Haustein M, Suhr F, Bloch W, Reppel M, Saric T, Wernig M, Janisch R, Brockmeier K, Hescheler J, Pillekamp F: Comparison of contractile behavior of native murine ventricular tissue and cardiomyocytes derived from embryonic or induced pluripotent stem cells. FASEB J 2010, 24: 2739–2751. 10.1096/fj.09-145177

  85. 85.

    Gupta MK, Illich DJ, Gaarz A, Matzkies M, Nguemo F, Pfannkuche K, Liang H, Classen S, Reppel M, Schultze JL, Hescheler J, Saric T: Global transcriptional profiles of beating clusters derived from human induced pluripotent stem cells and embryonic stem cells are highly similar. BMC Dev Biol 2010, 10: 98. 10.1186/1471-213X-10-98

  86. 86.

    Chan SS, Li HJ, Hsueh YC, Lee DS, Chen JH, Hwang SM, Chen CY, Shih E, Hsieh PC: Fibroblast growth factor-10 promotes cardiomyocyte differentiation from embryonic and induced pluripotent stem cells. PLoS ONE 2010, 5: e14414. 10.1371/journal.pone.0014414

  87. 87.

    Fujiwara M, Yan P, Otsuji TG, Narazaki G, Uosaki H, Fukushima H, Kuwahara K, Harada M, Matsuda H, Matsuoka S, Okita K, Takahashi K, Nakagawa M, Ikeda T, Sakata R, Mummery CL, Nakatsuji N, Yamanaka S, Nakao K, Yamashita JK: Induction and enhancement of cardiac cell differentiation from mouse and human induced pluripotent stem cells with cyclosporin-A. PLoS ONE 2011, 6: e16734. 10.1371/journal.pone.0016734

  88. 88.

    Zwi-Dantsis L, Mizrahi I, Arbel G, Gepstein A, Gepstein L: Scalable production of cardiomyocytes derived from c-Myc free induced pluripotent stem cells. Tissue Eng Part A 2011, 17: 1027–1037.

  89. 89.

    Quattrocelli M, Palazzolo G, Agnolin I, Martino S, Bouche M, Anastasia L, Sampaolesi M: Synthetic sulfonyl-hydrazone-1 positively regulates cardiomyogenic microRNA expression and cardiomyocyte differentiation of induced pluripotent stem cells. J Cell Biochem 2011, 112: 2006–2014. 10.1002/jcb.23118

  90. 90.

    So KH, Han YJ, Park HY, Kim JG, Sung DJ, Bae YM, Yang BC, Park SB, Chang SK, Kim EY, Park SP: Generation of functional cardiomyocytes from mouse induced pluripotent stem cells. Int J Cardiol 2011, 153: 277–285. 10.1016/j.ijcard.2010.08.052

  91. 91.

    Min JY, Yang Y, Converso KL, Liu L, Huang Q, Morgan JP, Xiao YF: Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. J Appl Physiol 2002, 92: 288–296. 10.1063/1.1481962

  92. 92.

    Cho SW, Gwak SJ, Kim IK, Cho MC, Hwang KK, Kwon JS, Choi CY, Yoo KJ, Kim BS: Granulocyte colony-stimulating factor treatment enhances the efficacy of cellular cardiomyoplasty with transplantation of embryonic stem cell-derived cardiomyocytes in infarcted myocardium. Biochem Biophys Res Commun 2006, 340: 573–582. 10.1016/j.bbrc.2005.12.044

  93. 93.

    Glass C, Singla DK: Overexpression of TIMP-1 in embryonic stem cells attenuates adverse cardiac remodeling following myocardial infarction. Cell Transplant 2012, 21: 1931–1944. 10.3727/096368911X627561

  94. 94.

    Caspi O, Lesman A, Basevitch Y, Gepstein A, Arbel G, Habib IH, Gepstein L, Levenberg S: Tissue engineering of vascularized cardiac muscle from human embryonic stem cells. Circ Res 2007, 100: 263–272. 10.1161/01.RES.0000257776.05673.ff

  95. 95.

    Li Z, Wilson KD, Smith B, Kraft DL, Jia F, Huang M, Xie X, Robbins RC, Gambhir SS, Weissman IL, Wu JC: Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction. PLoS ONE 2009, 4: e8443. 10.1371/journal.pone.0008443

  96. 96.

    Rufaihah AJ, Haider HK, Heng BC, Ye L, Tan RS, Toh WS, Tian XF, Sim EK, Cao T: Therapeutic angiogenesis by transplantation of human embryonic stem cell-derived CD133+ endothelial progenitor cells for cardiac repair. Regen Med 2010, 5: 231–244. 10.2217/rme.09.83

  97. 97.

    Simpson DL, Boyd NL, Kaushal S, Stice SL, Dudley SC Jr: Use of human embryonic stem cell derived-mesenchymal cells for cardiac repair. Biotechnol Bioeng 2012, 109: 274–283. 10.1002/bit.23301

  98. 98.

    Ahmed RP, Ashraf M, Buccini S, Shujia J, Haider H: Cardiac tumorigenic potential of induced pluripotent stem cells in an immunocompetent host with myocardial infarction. Regen Med 2011, 6: 171–178. 10.2217/rme.10.103

  99. 99.

    Zhang Y, Wang D, Chen M, Yang B, Zhang F, Cao K: Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart. PLoS ONE 2011, 6: e19012. 10.1371/journal.pone.0019012

  100. 100.

    Templin C, Zweigerdt R, Schwanke K, Olmer R, Ghadri JR, Emmert MY, Muller E, Kuest SM, Cohrs S, Schibli R, Kronen P, Hilbe M, Reinisch A, Strunk D, Haverich A, Hoerstrup S, Luscher TF, Kaufmann PA, Landmesser U, Martin U: Transplantation and tracking of human-induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment, and distribution by hybrid single photon emission computed tomography/computed tomography of sodium iodide symporter transgene expression. Circulation 2012, 126: 430–439. 10.1161/CIRCULATIONAHA.111.087684

  101. 101.

    Mauritz C, Martens A, Rojas SV, Schnick T, Rathert C, Schecker N, Menke S, Glage S, Zweigerdt R, Haverich A, Martin U, Kutschka I: Induced pluripotent stem cell (iPSC)-derived Flk-1 progenitor cells engraft, differentiate, and improve heart function in a mouse model of acute myocardial infarction. Eur Heart J 2011, 32: 2634–2641. 10.1093/eurheartj/ehr166

  102. 102.

    Dai B, Huang W, Xu M, Millard RW, Gao MH, Hammond HK, Menick DR, Ashraf M, Wang Y: Reduced collagen deposition in infarcted myocardium facilitates induced pluripotent stem cell engraftment and angiomyogenesis for improvement of left ventricular function. J Am Coll Cardiol 2011, 58: 2118–2127. 10.1016/j.jacc.2011.06.062

  103. 103.

    Fu W, Wang SJ, Zhou GD, Liu W, Cao Y, Zhang WJ: Residual undifferentiated cells during differentiation of induced pluripotent stem cells in vitro and in vivo. Stem Cells Dev 2011, 21: 521–529.

  104. 104.

    Zhao T, Zhang ZN, Rong Z, Xu Y: Immunogenicity of induced pluripotent stem cells. Nature 2011, 474: 212–215. 10.1038/nature10135

  105. 105.

    Song H, Yoon C, Kattman SJ, Dengler J, Masse S, Thavaratnam T, Gewarges M, Nanthakumar K, Rubart M, Keller GM, Radisic M, Zandstra PW: Interrogating functional integration between injected pluripotent stem cell-derived cells and surrogate cardiac tissue. Proc Natl Acad Sci USA 2010, 107: 3329–3334. 10.1073/pnas.0905729106

  106. 106.

    Lee G, Papapetrou EP, Kim H, Chambers SM, Tomishima MJ, Fasano CA, Ganat YM, Menon J, Shimizu F, Viale A, Tabar V, Sadelain M, Studer L: Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs. Nature 2009, 461: 402–406. 10.1038/nature08320

  107. 107.

    Lee G, Studer L: Modelling familial dysautonomia in human induced pluripotent stem cells. Philos Trans R Soc Lond B Biol Sci 2011, 366: 2286–2296. 10.1098/rstb.2011.0026

  108. 108.

    Esteban MA, Wang T, Qin B, Yang J, Qin D, Cai J, Li W, Weng Z, Chen J, Ni S, Chen K, Li Y, Liu X, Xu J, Zhang S, Li F, He W, Labuda K, Song Y, Peterbauer A, Wolbank S, Redl H, Zhong M, Cai D, Zeng L, Pei D: Vitamin C enhances the generation of mouse and human induced pluripotent stem cells. Cell Stem Cell 2010, 6: 71–79. 10.1016/j.stem.2009.12.001

  109. 109.

    Ieda M: Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Nihon Rinsho 2011,69(Suppl 7):524–527.

  110. 110.

    Corti S, Nizzardo M, Simone C, Falcone M, Donadoni C, Salani S, Rizzo F, Nardini M, Riboldi G, Magri F, Zanetta C, Faravelli I, Bresolin N, Comi GP: Direct reprogramming of human astrocytes into neural stem cells and neurons. Exp Cell Res 2012, 318: 1528–1541. 10.1016/j.yexcr.2012.02.040

Download references


This work is funded by Key Program of National Natural Science Foundation of China (No. 31030032); National Natural Science Funds for Distinguished Young Scholar (No. 31125013); National High Technology Research and Development Program of China (No. 2012AA020506); National Natural Science Foundation of China (No. 81101160).

Author information



Corresponding author

Correspondence to Changyong Wang.

Additional information

Competing interests

The authors declared that they have no competing interest.

Authors’ contributions

LZQ, ZJ, WHB and ZMG drafted the manuscript; WCY guided the writing and made revisions of the manuscript. All authors read and approved the final manuscript.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, Z., Zhou, J., Wang, H. et al. Current status of induced pluripotent stem cells in cardiac tissue regeneration and engineering. Regen Med Res 1, 6 (2013).

Download citation


  • Cell therapy
  • iPSCs
  • Myocardial infarction
  • Regenerative medicine
  • Tissue engineering