Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy

Efe, Jem; Hilcove, Simon; Kim, Jang Hwan; Zhou, Haoming; Ouyang, Kunfu; Wang, Gang; Chen, Ju; Ding, Sheng

doi:10.1038/ncb2164

Cited by 586 publications

(570 citation statements)

References 36 publications

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“…In contrast, we believe that lineage reprogramming using target cell-type-specific transcription factors represents direct conversion (i.e., transdifferentiation) without involving an intermediate pluripotent state. Consistent with this hypothesis, c-Myc was required for the dedifferentiation approach (21), presumably because without c-Myc the induction of pluripotency is decreased by orders of magnitude (31,32), and cell types representing a different germ layer, such as cardiomyocytes, can be achieved from a similar transient pluripotent state (20). Future studies will be required to determine whether specific NPC populations with defined differentiation potential, as shown here, can be generated using the transient dedifferentiation approach.…”

Section: Discussionmentioning

confidence: 72%

“…Following the seminal work of induced pluripotent stem (iPS) cell reprogramming (19), it was shown that transient expression of the four iPS cell reprogramming factors Oct4, Sox2, Klf4, and c-Myc followed by treatment with specific media succeeded in generating both cardiomyocytes and neural precursor cell (NPC) populations from fibroblasts (20,21). However, in these experiments the NPCs were generated with low efficiency (presumably because of inefficient induction of pluripotency and the stochastic nature of differentiation), the described cells could not self-renew, and the NPCs apparently lacked the ability to differentiate into oligodendrocytes.…”

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confidence: 99%

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Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells

Lujan

Chanda²,

Ahlenius³

et al. 2012

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

406

353

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We recently showed that defined sets of transcription factors are sufficient to convert mouse and human fibroblasts directly into cells resembling functional neurons, referred to as "induced neuronal" (iN) cells. For some applications however, it would be desirable to convert fibroblasts into proliferative neural precursor cells (NPCs) instead of neurons. We hypothesized that NPC-like cells may be induced using the same principal approach used for generating iN cells. Toward this goal, we infected mouse embryonic fibroblasts derived from Sox2-EGFP mice with a set of 11 transcription factors highly expressed in NPCs. Twenty-four days after transgene induction, Sox2-EGFP + colonies emerged that expressed NPC-specific genes and differentiated into neuronal and astrocytic cells. Using stepwise elimination, we found that Sox2 and FoxG1 are capable of generating clonal self-renewing, bipotent induced NPCs that gave rise to astrocytes and functional neurons. When we added the Pou and Homeobox domain-containing transcription factor Brn2 to Sox2 and FoxG1, we were able to induce tripotent NPCs that could be differentiated not only into neurons and astrocytes but also into oligodendrocytes. The transcription factors FoxG1 and Brn2 alone also were capable of inducing NPC-like cells; however, these cells generated less mature neurons, although they did produce astrocytes and even oligodendrocytes capable of integration into dysmyelinated Shiverer brain. Our data demonstrate that direct lineage reprogramming using target cell-type-specific transcription factors can be used to induce NPC-like cells that potentially could be used for autologous cell transplantation-based therapies in the brain or spinal cord.induced neural precursor cells D uring development, the creation of distinct cell types depends upon tightly regulated spatiotemporal expression of lineage-specific transcription factors. A key question is whether cells retain their competence to respond to such transcription factors even after differentiation and after their cell-type-specific phenotype has been stabilized by epigenetic mechanisms (1). A number of classic and recent studies have provided powerful evidence that the differentiated state of at least some somatic cells is more flexible than assumed. For instance, transfer of somatic nuclei into oocytes has been shown to impose an early embryonic program on somatic cells (2, 3). Similarly, aberrant cell-type-specific genes could be induced following cell fusion (4), and misexpression of defined transcription factors has been shown to induce conversion of cells in closely related cell types (5). For instance, the basic helix-loop-helix (bHLH) transcription factor MyoD has been shown to induce muscle-specific properties in fibroblasts but not in hepatocytes (6, 7); expression of Cebpα in B cells induces features of macrophages (8); loss of Pax5 in B cells induces dedifferentiation to a common lymphoid progenitor (9); and the bHLH transcription factor Ngn3 or NeuroD1, in combination with Pdx1 and MafA, efficientl...

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Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 99%

Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells

Lujan

Chanda²,

Ahlenius³

et al. 2012

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

406

353

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show abstract

“…For example, during dedifferentiation, the addition of a JAK inhibitor can inhibit long-term expression of exogenous transcription factors including Oct-4, Sox2, Klf4 and c-Myc, which will block further dedifferentiation from an unstable intermediate to an iPS cell [24]. Small molecules have an enormous potential to facilitate the application of lineage reprogramming.…”

Section: Application Prospects Of Lineage Reprogrammingmentioning

confidence: 99%

“…The use and combinations of iPS reprogramming factors are not the same for distinct target cells. For example, forced expression of a single transcription factor, Oct-4, allows the generation of an intermediate population that gives rise to blood lineages [22], whereas at least three factors including Oct-4, which is indispensable, are required for cell conversion to cardiac and neural cells [24,25]. However, Their et al [26] reported that constitutive induction of Sox2, Klf4, and c-Myc while strictly limiting Oct-4 activity to the initial phase of reprogramming allows the generation of stably expandable neural stem cells (NSCs).…”

Section: Dedifferentiationmentioning

confidence: 99%

Advances in cell lineage reprogramming

Zhou¹,

Yue²,

Pei³

2013

Sci. China Life Sci.

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As a milestone breakthrough of stem cell and regenerative medicine in recent years, somatic cell reprogramming has opened up new applications of regenerative medicine by breaking through the ethical shackles of embryonic stem cells. However, induced pluripotent stem (iPS) cells are prepared with a complicated protocol that results in a low reprogramming rate. To obtain differentiated target cells, iPS cells and embryonic stem cells still need to be induced using step-by-step procedures. The safety of induced target cells from iPS cells is currently a further concerning matter. More broadly conceived is lineage reprogramming that has been investigated since 1987. Adult stem cell plasticity, which triggered interest in stem cell research at the end of the last century, can also be included in the scope of lineage reprogramming. With the promotion of iPS cell research, lineage reprogramming is now considered as one of the most promising fields in regenerative medicine, will hopefully lead to customized, personalized therapeutic options for patients in the future.

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“…Some pluripotency factors used to produce iPSC can directly reprogram some cell types such as cardiomyocytes (Efe et al, 2011), neural stem cells or progenitors , angioblast-like progenitor cells (Kurian et al, 2013), endothelial cells (Li et al, 2013a), pancreatic lineages , and hepatocytes . Ma et al (2013) showed that pluripotent factors can reprogram adult cells into pluripotent cells with multiple steps and that at certain steps some cells' fates are formed as transition stages of epigenetic reprogramming .…”

Section: Pluripotency Factors For Indirect Reprogrammingmentioning

confidence: 99%

Direct reprogramming of somatic cells: an update

Pham

2015

Biomed Res Ther

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Abstract-Direct epigenetic reprogramming is a technique that converts a differentiated adult cell into another differentiated cell-such fibroblasts to cardiomyocytes-without passage through an undifferentiated pluripotent stage. This novel technology is opening doors in biological research and regenerative medicine. Some preliminary studies about direct reprogramming started in the 1980s when differentiated adult cells could be converted into other differentiated cells by overexpressing transcription-factor genes. These studies also showed that differentiated cells have plasticity. Direct reprogramming can be a powerful tool in biological research and regenerative medicine, especially the new frontier of personalized medicine. This review aims to summarize all direct reprogramming studies of somatic cells by master control genes as well as potential applications of these techniques in research and treatment of selected human diseases.

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Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy

Cited by 586 publications

References 36 publications

Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells

Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells

Advances in cell lineage reprogramming

Direct reprogramming of somatic cells: an update

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