Evidence map›Paper›PMID 25077947›Full record

ArticleCirculation. Cardiovascular genetics2014

iPS cell-derived cardiogenicity is hindered by sustained integration of reprogramming transgenes.

Almudena Martinez-Fernandez, Timothy J Nelson, Santiago Reyes, Alexey E Alekseev, Frank Secreto, Carmen Perez-Terzic, Rosanna Beraldi, Hoon-Ki Sung, Andras Nagy, Andre Terzic

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation. Cardiovascular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.7field-weighted citation impact, top 29% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 11 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Review
  5. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 1 institution in 2 countries.

Almudena Martinez-FernandezFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Timothy J NelsonFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Santiago ReyesFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Alexey E AlekseevFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Frank SecretoFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Carmen Perez-TerzicFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Rosanna BeraldiFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Hoon-Ki SungFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Andras NagyFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.).
Andre TerzicFrom the Center for Regenerative Medicine (A.M.-F., T.J.N., S.R., A.E.A., A.T.), Marriott Heart Disease Research Program, Division of Cardiovascular Diseases (A.M.-F., S.R., A.E.A., A.T.), and Department of Physical Medicine and Rehabilitation (C.P.-T.), General Internal Medicine and Transplant Center (T.J.N., F.S., R.B.), Mayo Clinic, Rochester, MN; and Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (H.-K.S., A.N.). terzic.andre@mayo.edu.
Lunenfeld-Tanenbaum Research Institute · CA

Funding

Cardioprotective Repair through CardiopoiesisR01HL083439 · NHLBI · MAYO CLINIC ROCHESTER · PI TERZIC, ANDRE · 2006 to 2010
$1.8M
NHLBI NIH HHS R01 HL083439
6 · The paper itself

Abstract

backgroundNuclear reprogramming inculcates pluripotent capacity by which de novo tissue differentiation is enabled. Yet, introduction of ectopic reprogramming factors may desynchronize natural developmental schedules. This study aims to evaluate the effect of imposed transgene load on the cardiogenic competency of induced pluripotent stem (iPS) cells. METHODS AND

resultsTargeted inclusion and exclusion of reprogramming transgenes (c-MYC, KLF4, OCT4, and SOX2) was achieved using a drug-inducible and removable cassette according to the piggyBac transposon/transposase system. Pulsed transgene overexpression, before iPS cell differentiation, hindered cardiogenic outcomes. Delayed in counterparts with maintained integrated transgenes, transgene removal enabled proficient differentiation of iPS cells into functional cardiac tissue. Transgene-free iPS cells generated reproducible beating activity with robust expression of cardiac α-actinin, connexin 43, myosin light chain 2a, α/β-myosin heavy chain, and troponin I. Although operational excitation-contraction coupling was demonstrable in the presence or absence of transgenes, factor-free derivatives exhibited an expedited maturing phenotype with canonical responsiveness to adrenergic stimulation.

conclusionsA disproportionate stemness load, caused by integrated transgenes, affects the cardiogenic competency of iPS cells. Offload of transgenes in engineered iPS cells ensures integrity of cardiac developmental programs, underscoring the value of nonintegrative nuclear reprogramming for derivation of competent cardiogenic regenerative biologics.

Indexed as

TransgenesActininAnimalsCardiac MyosinsCell DifferentiationCell SeparationCellular ReprogrammingConnexin 43ElectrophysiologyFibroblastsFlow CytometryGenetic TechniquesInduced Pluripotent Stem CellsKruppel-Like Factor 4MiceMicroscopy, ElectronActininCardiac MyosinsConnexin 43Klf4 protein, mouseKruppel-Like Factor 4Myosin Heavy Chainsmyosin light chain 2Myosin Light ChainsTroponin Iinduced pluripotent stem cellsnuclear reprogrammingregenerationregenerative medicinestem cells

Identifiers

PMID25077947
PMCPMC4273857
OpenAlexW2320379450

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.