Developmental expression of troponin I isoforms in fetal human heart

Bhavsar, Pankaj; Dhoot, Gurtej K.; Cumming, D. V. E.; Butler-Browne, Gillian; Yacoub, Magdi H.; Barton, Paul J.R.

doi:10.1016/0014-5793(91)80820-s

Cited by 93 publications

(19 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[18, 47, 48] Importantly, Metzger and colleagues have shown that the troponin complex in human iPSC-CMs are comprised largely of ssTnI even after 9 months of culture. [49].…”

Section: Resultsmentioning

confidence: 99%

“…[18, 47] According to our Western analysis, culturing iPSC-CMs on 4%PEG-96%PCL for 30 days dramatically increased cTnI:ssTnI ratio to approximately 70:30, which was not achieved in human iPSC-CMs even after 9 months of culture. [18, 47] Immunostaining with cTnI suggests that the increase in cTni:ssTnI ratio may reflect a ssTnI to cTnI switch in a subset of iPSC_CMs maintained on 4%PEG-96%PCL. Finally, the fraction of cells that expressed MLC-2v was about 5-fold higher for 30-day old iPSC-CMs maintain on 4%PEG-96%PCL than for 100-day old iPSC-CMs maintained on traditional substrates like Matrigel.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes

et al. 2015

View full text Add to dashboard Cite

Cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) hold great promise for modeling human heart diseases. However, iPSC-CMs studied to date resemble immature embryonic myocytes and therefore do not adequately recapitulate native adult cardiomyocyte phenotypes. Since extracellular matrix plays an essential role in heart development and maturation in vivo, we sought to develop a synthetic culture matrix that could enhance functional maturation of iPSC-CMs in vitro. In this study, we employed a library of combinatorial polymers comprising of three functional subunits - poly-ε-caprolacton (PCL), polyethylene glycol (PEG), and carboxylated PCL (cPCL) - as synthetic substrates for culturing human iPSC-CMs. Of these, iPSC-CMs cultured on 4%PEG-96%PCL (each % indicates the corresponding molar ratio) exhibit the greatest contractility and mitochondrial function. These functional enhancements are associated with increased expression of cardiac myosin light chain-2v, cardiac troponin I and integrin alpha-7. Importantly, iPSC-CMs cultured on 4%PEG-95%PCL demonstrate troponin I (TnI) isoform switch from the fetal slow skeletal TnI (ssTnI) to the postnatal cardiac TnI (cTnI), the first report of such transition in vitro. Finally, culturing iPSC-CMs on 4%PEG-96%PCL also significantly increased expression of genes encoding intermediate filaments known to transduce integrin-mediated mechanical signals to the myofilaments. In summary, our study demonstrates that synthetic culture matrices engineered from combinatorial polymers can be utilized to promote in vitro maturation of human iPSC-CMs through the engagement of critical matrix-integrin interactions.

show abstract

“…[18, 47, 48] Importantly, Metzger and colleagues have shown that the troponin complex in human iPSC-CMs are comprised largely of ssTnI even after 9 months of culture. [49].…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In this light, we propose that the developmentally controlled and irreversible genetic switch in the sarcomeric TNNI genes provides an excellent marker to track the differentiation status of stem cell-derived cardiac myocytes. Owing to strict developmental control in all mammalian hearts, including humans, the programmed inactivation of the “fetal” TNNI gene product, ssTnI, together in exquisite temporal concert with stoichiometric replacement by the adult gene product, cTnI, represents a unique molecular marker of cardiac myocyte maturation status (Bhavsar et al., 1991). …”

Section: Discussionmentioning

confidence: 99%

Acquisition of a Quantitative, Stoichiometrically Conserved Ratiometric Marker of Maturation Status in Stem Cell-Derived Cardiac Myocytes

et al. 2014

View full text Add to dashboard Cite

SummaryThere is no consensus in the stem cell field as to what constitutes the mature cardiac myocyte. Thus, helping formalize a molecular signature for cardiac myocyte maturation would advance the field. In the mammalian heart, inactivation of the “fetal” TNNI gene, TNNI1 (ssTnI), together in temporal concert with its stoichiometric replacement by the adult TNNI gene product, TNNI3 (cTnI), represents a quantifiable ratiometric maturation signature. We examined the TNNI isoform transition in human induced pluripotent stem cell (iPSC) cardiac myocytes (hiPSC-CMs) and found the fetal TNNI signature, even during long-term culture. Rodent stem cell-derived and primary myocytes, however, transitioned to the adult TnI profile. Acute genetic engineering of hiPSC-CMs enabled a rapid conversion toward the mature TnI profile. While there is no single marker to denote the mature cardiac myocyte, we propose that tracking the cTnI:ssTnI protein isoform ratio provides a valuable maturation signature to quantify myocyte maturation status across laboratories.

show abstract

“…The cardiac troponin I is unique to cardiac muscle. The skeletal muscle, both in experimental animals and humans, does not express cardiac troponin I at any developmental stage or reexpress it in response to any pathological stimuli [30, 31, 32, 33, 34]. Therefore, cardiac troponin I was reported to be very specific in chronic renal failure, especially with the monoclonal antibody assay that does not cross-react with the skeletal muscle isoform [27, 28, 29].…”

Section: Discussionmentioning

confidence: 99%

“…Since cardiac troponin I is exclusively of cardiac origin and, unlike creatine kinase-MB isoenzyme and cardiac troponin T, does not express in the skeletal muscle at any developmental stage [30, 31, 32, 33, 34], it has been shown to be more specific for the detection of myocardial injury in chronic renal failure patients [21, 22, 23, 29]. However, there are very few well-controlled studies evaluating the specificity of cardiac troponin I and creatine kinase-MB isoenzyme in ambulatory asymptomatic chronic renal failure patients on long-term hemodialysis, and evaluating the effect of hemodialysis on serum levels of cardiac troponin I and creatine kinase-MB isoenzyme.…”

Section: Introductionmentioning

confidence: 99%

Specificity of Cardiac Troponin I and Creatine Kinase-MB Isoenzyme in Asymptomatic Long-Term Hemodialysis Patients and Effect of Hemodialysis on These Cardiac Markers

et al. 1998

View full text Add to dashboard Cite

Objectives: The objectives of this study were: (1) to evaluate the specificity of cardiac troponin I and creatine kinase-MB isoenzyme in ambulatory asymptomatic chronic renal failure patients on long-term hemodialysis, and (2) to evaluate the effect of hemodialysis on the serum levels of cardiac troponin I and creatine kinase-MB isoenzyme. Methods: One hundred and forty-four consecutive ambulatory asymptomatic chronic renal failure patients on hemodialysis for a minimum of 1 year were evaluated clinically. Serum cardiac troponin I and creatine kinase-MB isoenzyme levels were measured with specific monoclonal antibodies before and after dialysis using ACCESS Troponin I and ACCESS CK-MB assays. Results: The specificity of serum cardiac troponin I was 83% with a cutoff level of 0.03 ng/ml, which is an expected level for healthy population, but it rose to 100% with a cutoff level of 0.15 ng/ml, which is a reference level for patients with acute myocardial infarction. Twenty-four (17%) patients had borderline elevation in cardiac troponin I (>0.03 to <0.15 ng/ml). A history of angina pectoris was more common in the borderline-elevated cardiac troponin I subgroup. In 28% of the patients, serum creatine kinase-MB isoenzyme levels were increased with a specificity of 72% at a cutoff level of 4 ng/ml, which is the upper limit of normal, but the specificity rose to 98% by increasing the cutoff level value to 10 ng/ml. There were no statistically significant differences in serum levels of cardiac troponin I and creatine kinase-MB isoenzyme before and after dialysis. Conclusions: Cardiac troponin I is highly specific in ambulatory asymptomatic chronic renal failure patients on long-term hemodialysis; borderline elevations in cardiac troponin I may represent microinjury to the myocardium. A serum level of creatine kinase-MB isoenzyme >2.5 times of the normal upper limit may be highly specific in this patient population. Hemodialysis per se does not significantly change the serum levels of cardiac troponin I and creatine kinase-MB isoenzyme.

show abstract

Developmental expression of troponin I isoforms in fetal human heart

Cited by 93 publications

References 29 publications

Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes

Combinatorial polymer matrices enhance in vitro maturation of human induced pluripotent stem cell-derived cardiomyocytes

Acquisition of a Quantitative, Stoichiometrically Conserved Ratiometric Marker of Maturation Status in Stem Cell-Derived Cardiac Myocytes

Specificity of Cardiac Troponin I and Creatine Kinase-MB Isoenzyme in Asymptomatic Long-Term Hemodialysis Patients and Effect of Hemodialysis on These Cardiac Markers

Contact Info

Product

Resources

About