This is a free review (for now...) from Cell Stem Cells, about the study of regenerative mechanisms in the heart. It discusses the use of endogenous adult stem cell populations alongside the recent application of reprogramming technologies for the development of therapies targeting heart disease.
In this open-access short review, Liu. et al, discuss the achievements and current status of induced pluripotent stem cells (iPSC) for cardiac tissue regeneration, 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.
To learn about heart development, stem cell differentiation protocols, and cell therapies:
Summary: Direct reprogramming of adult somatic cells into alternative cell types has been shown for several lineages. We previously showed that GATA4, MEF2C, and TBX5 (GMT) directly reprogrammed nonmyocyte mouse heart cells into induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. However, GMT alone appears insufficient in human fibroblasts, at least in vitro. Here, we show that GMT plus ESRRG and MESP1 induced global cardiac gene-expression and phenotypic shifts in human fibroblasts derived from embryonic stem cells, fetal heart, and neonatal skin. Adding Myocardin and ZFPM2 enhanced reprogramming, including sarcomere formation, calcium transients, and action potentials, although the efficiency remained low. Human iCM reprogramming was epigenetically stable. Furthermore, we found that transforming growth factor β signaling was important for, and improved the efficiency of, human iCM reprogramming. These findings demonstrate that human fibroblasts can be directly reprogrammed toward the cardiac lineage, and lay the foundation for future refinements in vitro and in vivo.
Jacob Blumenthal's insight:
In this paper, the researchers use direct differentiation methods to differentiate fibroblasts into cardiomyocyte-like cells. First, they do a screening analysis to find the most effective cocktail of transcription factor for the reprogramming. Then, they explore the gene expression of the induced cardiomtocytes, including their epigenetic state. Taken together, this paper adds important information regarding the transcription factors and signal pathways that are important to establish the identity of cardiomyocytes, which may lead in the future to the development of patient-specific therapies for heart diseases.
In a new paper published this week online in Nature, a team from the Perelman School of Medicine, University of Pennsylvania, shows that the pulmonary vasculature, the blood vessels that connect the heart to the lung, develops even in the absence of the lung. Mice in which lung development is inhibited still have pulmonary blood vessels, which revealed to the researchers that cardiac progenitors, or stem cells, are essential for cardiopulmonary co-development.
Jacob Blumenthal's insight:
In a paper published online in Nature, the researchers show that the murine pulmonary vasculature develops even in the absence of lung development. They have identified a population of multipotent cardiopulmonary mesoderm progenitors (CPPs) within the posterior pole of the heart that are marked by the expression of Wnt2, Gli1 and Isl1. In addition, they demonstrated that CPPs arise from cardiac progenitors before lung development. They found that CPPs are regulated by hedgehog expression from the foregut endoderm, which is required for connection of the pulmonary vasculature to the heart.
From the abstract: "In 'Bedside to Bench', Christine L. Mummery and Richard T. Lee lay out a framework for re-evaluating cardiac cell therapies in the context of two recent clinical trials, in which autologous cardiac stem cells derived from heart biopsies were transferred into patients, with promising, albeit difficult to interpret, results. In 'Bench to Bedside', Young-Jae Nam, Kunhua Song and Eric N. Olson discuss a number of recent studies in rodents showing that cardiac fibroblasts can be reprogrammed, via miRNAs and a transcription factor 'cocktail', to express cardiac genes, which resulted in improved cardiac function in the animals, suggesting a new way forward for fixing damaged heart tissue."
Cardiomyocytes, differentiated from either human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs), are used in cardiovascular research throughout the last decade. In addition to their regenerative capacities and promise for clinical application, these cells provide an unlimited source of...
When stem cells are used for the treatment of heart diseases, they usually have a short-term effect, mostly because they don't stay at the injection site or simply because they die. In order to overcome this problem, researchers from Emory university encapsulated mesenchymal stem cells (MSCs) in alginate-based capsules and inserted them into heart-attack rat models. They found that the rats that were treated with the encapsulated cells displayed increased heart function, reduced scar size and more growth of new blood vessels , compared to control rats that were treated by standard cell injection. In addition. more encapsulated cells remained viable.
This strategy can be used for other cell therapies, like transplantation of pluripotent stem cells-derived beta islets for the treatment of diabetes. Of course, in that case the main challenge will be to prevent the rejection of these cells, post transplantation.
Scientists from the University of Pittsburgh believe their breakthrough could lead to the development of transplant organs for patients thanks to stem cells produced from simple skin biopsies.
Jacob Blumenthal's insight:
Scientists generated heart constructs by repopulating decellularized mouse hearts with human induced pluripotent stem cell-derived multipotential cardiovascular progenitor cells. The cells migrate, proliferate and differentiate in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the decellularized hearts. After 20 days of perfusion, the engineered heart tissues exhibit spontaneous contractions, generate mechanical force and are responsive to drugs. This very interesting paper demonstrates the vast potential of the combination between tissue engineering 3D scaffolds, and stem cells differentiation. It was shown by others that decellularized tissues contain growth factor "pockets" or other imprinted csignals that allows recellularization of the tissue and differentiation of stem cells.