scholarly journals Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes

2021 ◽  
Vol 8 ◽  
Author(s):  
Chiara Bongiovanni ◽  
Francesca Sacchi ◽  
Silvia Da Pra ◽  
Elvira Pantano ◽  
Carmen Miano ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Cardiac Tissue ◽  
Neonatal Period ◽  
Adult Stem Cell ◽  
Stem Cell Differentiation ◽  
Cardiomyocyte Proliferation ◽  
Cardiac Muscle Cells ◽  
Wide Range

Despite considerable efforts carried out to develop stem/progenitor cell-based technologies aiming at replacing and restoring the cardiac tissue following severe damages, thus far no strategies based on adult stem cell transplantation have been demonstrated to efficiently generate new cardiac muscle cells. Intriguingly, dedifferentiation, and proliferation of pre-existing cardiomyocytes and not stem cell differentiation represent the preponderant cellular mechanism by which lower vertebrates spontaneously regenerate the injured heart. Mammals can also regenerate their heart up to the early neonatal period, even in this case by activating the proliferation of endogenous cardiomyocytes. However, the mammalian cardiac regenerative potential is dramatically reduced soon after birth, when most cardiomyocytes exit from the cell cycle, undergo further maturation, and continue to grow in size. Although a slow rate of cardiomyocyte turnover has also been documented in adult mammals, both in mice and humans, this is not enough to sustain a robust regenerative process. Nevertheless, these remarkable findings opened the door to a branch of novel regenerative approaches aiming at reactivating the endogenous cardiac regenerative potential by triggering a partial dedifferentiation process and cell cycle re-entry in endogenous cardiomyocytes. Several adaptations from intrauterine to extrauterine life starting at birth and continuing in the immediate neonatal period concur to the loss of the mammalian cardiac regenerative ability. A wide range of systemic and microenvironmental factors or cell-intrinsic molecular players proved to regulate cardiomyocyte proliferation and their manipulation has been explored as a therapeutic strategy to boost cardiac function after injuries. We here review the scientific knowledge gained thus far in this novel and flourishing field of research, elucidating the key biological and molecular mechanisms whose modulation may represent a viable approach for regenerating the human damaged myocardium.

scholarly journals Physicochemical Control of Adult Stem Cell Differentiation: Shedding Light on Potential Molecular Mechanisms

2010 ◽  
Vol 2010 ◽  
pp. 1-14 ◽  
Author(s):  
Igor Titushkin ◽  
Shan Sun ◽  
Jennifer Shin ◽  
Michael Cho
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Molecular Mechanisms ◽  
Adult Stem Cell ◽  
Stem Cell Differentiation ◽  
Cell Behavior ◽  
Soluble Factors ◽  
Multiple Differentiation ◽  
Exciting Potential ◽  
Physical Forces

Realization of the exciting potential for stem-cell-based biomedical and therapeutic applications, including tissue engineering, requires an understanding of the cell-cell and cell-environment interactions. To this end, recent efforts have been focused on the manipulation of adult stem cell differentiation using inductive soluble factors, designing suitable mechanical environments, and applying noninvasive physical forces. Although each of these different approaches has been successfully applied to regulate stem cell differentiation, it would be of great interest and importance to integrate and optimally combine a few or all of the physicochemical differentiation cues to induce synergistic stem cell differentiation. Furthermore, elucidation of molecular mechanisms that mediate the effects of multiple differentiation cues will enable the researcher to better manipulate stem cell behavior and response.

Wide-range stiffness gradient PVA/HA hydrogel to investigate stem cell differentiation behavior

2016 ◽  
Vol 35 ◽  
pp. 23-31 ◽  
Author(s):  
Se Heang Oh ◽  
Dan Bi An ◽  
Tae Ho Kim ◽  
Jin Ho Lee
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Wide Range

Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes

2003 ◽  
Vol 285 (6) ◽  
pp. H2355-H2363 ◽  
Author(s):  
Mirit Snir ◽  
Izhak Kehat ◽  
Amira Gepstein ◽  
Raymond Coleman ◽  
Joseph Itskovitz-Eldor ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Embryonic Stem Cell ◽  
Late Stage ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Es Cell ◽  
Cardiomyocyte Proliferation ◽  
Ki 67

Assessment of early ultrastructural development and cell-cycle regulation in human cardiac tissue is significantly hampered by the lack of a suitable in vitro model. Here we describe the possible utilization of human embryonic stem cell (ES) lines for investigation of these processes. With the use of the embryoid body (EB) differentiation system, human ES cell-derived cardiomyocytes at different developmental stages were isolated and their histomorphometric, ultrastructural, and proliferative properties were characterized. Histomorphometric analysis revealed an increase in cell length, area, and length-to-width ratio in late-stage EBs (>35 days) compared with early (10–21 days) and intermediate (21–35 days) stages. This was coupled with a progressive ultrastructural development from an irregular myofibrillar distribution to an organized sarcomeric pattern. Cardiomyocyte proliferation, assessed by double labeling with cardiac-specific antibodies and either [3H]thymidine incorporation or Ki-67 immunolabeling, demonstrated a gradual withdrawal from cell cycle. Hence, the percentage of positively stained nuclei in early-stage cardiomyocytes ([3H]thymidine: 60 ± 10%, Ki-67: 54 ± 23%) decreased to 36 ± 7% and 9 ± 16% in intermediate-stage EBs and to <1% in late-stage cardiomyocytes. In conclusion, a reproducible temporal pattern of early cardiomyocyte proliferation, cell-cycle withdrawal, and ultrastructural maturation was noted in this model. Establishment of this unique in vitro surrogate system may allow to examine the molecular mechanisms underlying these processes and to assess interventions aiming to modify these properties. Moreover, the detailed characterization of the ES cell-derived cardiomyocyte may be crucial for the development of future cell replacement strategies aiming to regenerate functional myocardium.

scholarly journals Unraveling the Control of Cell Cycle Periods during Intestinal Stem Cell Differentiation

2018 ◽  
Vol 115 (11) ◽  
pp. 2250-2258 ◽  
Author(s):  
Richard Ballweg ◽  
Suengwon Lee ◽  
Xiaonan Han ◽  
Philip K. Maini ◽  
Helen Byrne ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Intestinal Stem Cell

scholarly journals A Branching Process to Characterize the Dynamics of Stem Cell Differentiation

2015 ◽  
Author(s):  
david miguez
Keyword(s):  
Mathematical Model ◽  
Cell Cycle ◽  
Stem Cell ◽  
Cycle Length ◽  
Branching Process ◽  
Stem Cell Differentiation ◽  
Stem Cell Population ◽  
Mathematical Framework ◽  
Average Cell ◽  
Cell Cycle Length

The understanding of the regulatory processes that orchestrate stem cell maintenance is a cornerstone in developmental biology. Here, we present a mathematical model based on a branching process formalism that predicts average rates of proliferative and differentiative divisions in a given stem cell population. In the context of vertebrate spinal neurogenesis, the model predicts complex non-monotonic variations in the rates of pp, pd and dd modes of division as well as in cell cycle length, in agreement with experimental results. Moreover, the model shows that the differentiation probability follows a binomial distribution, allowing us to develop equations to predict the rates of each mode of division. A phenomenological simulation of the developing spinal cord informed with the average cell cycle length and division rates predicted by the mathematical model reproduces the correct dynamics of proliferation and differentiation in terms of average numbers of progenitors and differentiated cells. Overall, the present mathematical framework represents a powerful tool to unveil the changes in the rate and mode of division of a given stem cell pool by simply quantifying numbers of cells at different times.

Abstract 20492: Mlf1 Regulates Myocyte Proliferation in Postnatal Hearts

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Shalini Muralidhar ◽  
Feng Xiao ◽  
Suwannee Thet ◽  
Hesham Sadek
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Molecular Mechanisms ◽  
Gene Array ◽  
Bhlh Transcription Factor ◽  
Cardiomyocyte Proliferation ◽  
Regenerative Capacity ◽  
Cycle Arrest ◽  
Endogenous Expression

Lower vertebrates, such as newt and zebrafish, retain a robust cardiac regenerative capacity following injury. Although adult mammals lack this cardiac regenerative potential, there is ample interest in understanding how heart regeneration occurs, and to reawaken this process in adult humans. Recently, we showed that mice are capable of regenerating their hearts shortly after birth following injury. This regenerative response is associated with robust proliferation of cardiomyocytes without significant hypertrophy or fibrosis. However, this regenerative capacity is lost by 7 days postnatally, coinciding with cell cycle arrest. In an effort to determine the mechanism of cardiomyocytes cell cycle arrest after the first week of life, we performed a gene array after cardiac injury at multiple post-natal time points. This enabled us to identify a number of transcription factors that are differentially expressed during this postnatal window. We recently reported that one of these transcription factors Meis1 regulates postnatal cell cycle arrest of cardiomyocytes. Furthermore, Myeloid leukemia factor 1 (Mlf1), a bhlh transcription factor that has not been previously studied in the heart has similar dysregulated pattern following injury. Our preliminary data with in-vitro knockdown of Mlf1 in cardiomyocyte resulted in 2-fold increase in cardiomyocyte proliferation. Furthermore, immunohistochemistry results indicated that the endogenous expression and nuclear localization of Mlf1 in the post-natal cardiomyocytes coincides with cell cycle arrest. To explore this pattern, we generated a cardiomyocyte-specific Mlf1 knockout mouse, and showed that loss of Mlf1 results in robust cardiomyocyte proliferation in postnatal hearts (P14). Additionally, we confirmed previous reports that Mlf1 regulates p53 and induces cell cycle arrest by induction of CDK inhibitors like p21 and p57 in these Mlf1 KO mice. This suggests a role of Mlf1 in promoting reactivation of injured myocardium through induction of cardiomyocyte proliferation. These findings will further provide evidences of molecular mechanisms involved in the dormant regenerative capacity in adult mammals that can be a potential target of therapeutic approaches.

scholarly journals Gold Nanowires/Fibrin Nanostructure as Microfluidics Platforms for Enhancing Stem Cell Differentiation: Bio-AFM Study

Micromachines ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 50 ◽  
Author(s):  
Hashemzadeh ◽  
Allahverdi ◽  
Ghorbani ◽  
Soleymani ◽  
Kocsis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Physical Parameters ◽  
Gold Nanowires ◽  
Matrix Elasticity ◽  
Cell Chip ◽  
Chip Technology ◽  
Wide Range ◽  
Organ On A Chip

Organ-on-a-chip technology has gained great interest in recent years given its ability to control the spatio-temporal microenvironments of cells and tissues precisely. While physical parameters of the respective niche such as microchannel network sizes, geometric features, flow rates, and shear forces, as well as oxygen tension and concentration gradients, have been optimized for stem cell cultures, little has been done to improve cell-matrix interactions in microphysiological systems. Specifically, detailed research on the effect of matrix elasticity and extracellular matrix (ECM) nanotopography on stem cell differentiation are still in its infancy, an aspect that is known to alter a stem cell’s fate. Although a wide range of hydrogels such as gelatin, collagen, fibrin, and others are available for stem cell chip cultivations, only a limited number of elasticities are generally employed. Matrix elasticity and the corresponding nanotopography are key factors that guide stem cell differentiation. Given this, we investigated the addition of gold nanowires into hydrogels to create a tunable biointerface that could be readily integrated into any organ-on-a-chip and cell chip system. In the presented work, we investigated the matrix elasticity (Young’s modulus, stiffness, adhesive force, and roughness) and nanotopography of gold nanowire loaded onto fibrin hydrogels using the bio-AFM (atomic force microscopy) method. Additionally, we investigated the capacity of human amniotic mesenchymal stem cells (hAMSCs) to differentiate into osteo- and chondrogenic lineages. Our results demonstrated that nanogold structured-hydrogels promoted differentiation of hAMSCs as shown by a significant increase in Collagen I and II production. Additionally, there was enhanced calcium mineralization activity and proteoglycans formation after a cultivation period of two weeks within microfluidic devices.

scholarly journals Loss of foxo rescues stem cell aging in Drosophila germ line

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Filippo Artoni ◽  
Rebecca E Kreipke ◽  
Ondina Palmeira ◽  
Connor Dixon ◽  
Zachary Goldberg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Ionizing Radiation ◽  
Cell Injury ◽  
Germ Line ◽  
Adult Stem Cell ◽  
Cell Aging ◽  
Germline Stem Cells ◽  
Cell Cycle Reentry

Aging stem cells lose the capacity to properly respond to injury and regenerate their residing tissues. Here, we utilized the ability of Drosophila melanogaster germline stem cells (GSCs) to survive exposure to low doses of ionizing radiation (IR) as a model of adult stem cell injury and identified a regeneration defect in aging GSCs: while aging GSCs survive exposure to IR, they fail to reenter the cell cycle and regenerate the germline in a timely manner. Mechanistically, we identify foxo and mTOR homologue, Tor as important regulators of GSC quiescence following exposure to ionizing radiation. foxo is required for entry in quiescence, while Tor is essential for cell cycle reentry. Importantly, we further show that the lack of regeneration in aging germ line stem cells after IR can be rescued by loss of foxo.

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