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1. Differentiation of mouse embryonic fibroblasts (MEFs) into cardiomyocytes using human-derived cardiac inducing RNA (CIR).

   Lemanski, L.F. (April 2021, Stem cell and regenerative medicine)

   null (Ed.)

   The present study explores an RNA we have discovered in human heart that induces differentiation of mouse embryonic stem cells and human induced pluripotent stem cells into cardiomyocytes in vitro. We have designated this RNA as Cardiac Inducing RNA or CIR. We now find that CIR also induces mouse embryonic fibroblasts (MEF) to form cardiomyocytes in vitro. For these studies, human-derived CIR is transfected into MEF using lipofectamine. The CIR-transfected mouse fibroblasts exhibit spindle-shaped cells, characteristic of myocardial cells in culture, and express cardiac-specific troponin-T and cardiac tropomyosin. As such, the CIR-induced conversion of the fibroblasts into cardiomyocytes in vitro appears to take place without initial dedifferentiation into pluripotent stem cells. Instead, after CIR transfection using a lipofectamine transfection system, over the next 8 days there appears to be a direct transdifferentiation of ˃80% of the cultured fibroblasts into definitive cardiomyocytes. Fewer than ˂7% of the untreated controls using non-active RNA or lipofectamine by itself show cardiomyocyte characteristics. Thus, discovery of CIR may hold significant potential for future use in repair/regeneration of damaged myocardial tissue in humans after myocardial infarction or other disease processes such that affected patients may be able to return to pre-heart-disease activity levels. 

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2. Cardiomyogenic differentiation of human bone marrow‐derived mesenchymal stem cell spheroids within electrospun collagen nanofiber mats

   https://doi.org/10.1002/jbm.a.36530  

   Joshi, Jyotsna; Brennan, David; Beachley, Vince; Kothapalli, Chandrasekhar R. (September 2018, Journal of Biomedical Materials Research Part A)

   Abstract Collagen is the major structural protein in myocardium and contributes to tissue strength and integrity, cellular orientation, and cell–cell and cell‐matrix interactions. Significant post‐myocardial infarction related loss of cardiomyocytes and cardiac tissue, and their subsequent replacement with fibrous scar tissue, negatively impacts endogenous tissue repair and regeneration capabilities. To overcome such limitations, tissue engineers are working toward developing a 3D cardiac patch which not only mimics the structural, functional, and biological hierarchy of the native cardiac tissue, but also could deliver autologous stem cells and encourage their homing and differentiation. In this study, we examined the utility of electrospun, randomly‐oriented, type‐I collagen nanofiber (dia= 789 ± 162 nm) mats on the cardiomyogenic differentiation of human bone marrow‐derived mesenchymal stem cells (BM‐MSC) spheroids, in the presence or absence of 10 μM 5‐azacytidine (aza). Results showed that these scaffolds are biocompatible and enable time‐dependent evolution of early (GATA binding protein 4: GATA4), late (cardiac troponin I: cTnI), and mature (myosin heavy chain: MHC) cardiomyogenic markers, with a simultaneous reduction in CD90 (stemness) expression, independent of aza‐treatment. Aza‐exposure improved connexin‐4 expression and sustained sarcomeric α‐actin expression, but provided only transient improvement in cardiac troponin T (cTnT) expression. Cell orientation and alignment significantly improved in these nanofiber scaffolds over time and with aza‐exposure. Although further quantitativein vitroandin vivostudies are needed to establish the clinical applicability of such stem‐cell laden collagen nanofiber mats as cardiac patches for cardiac tissue regeneration, our results underscore the benefits of 3D milieu provided by electrospun collagen nanofiber mats, aza, and spheroids on the survival, cardiac differentiation and maturation of human BM‐MSCs. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3303–3312, 2018. 

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3. Stimuli-responsive biomaterials for cardiac tissue engineering and dynamic mechanobiology

   https://doi.org/10.1063/5.0025378  

   Shi, Huaiyu; Wang, Chenyan; Ma, Zhen (March 2021, APL Bioengineering)

   Since the term “smart materials” was put forward in the 1980s, stimuli-responsive biomaterials have been used as powerful tools in tissue engineering, mechanobiology, and clinical applications. For the purpose of myocardial repair and regeneration, stimuli-responsive biomaterials are employed to fabricate hydrogels and nanoparticles for targeted delivery of therapeutic drugs and cells, which have been proved to alleviate disease progression and enhance tissue regeneration. By reproducing the sophisticated and dynamic microenvironment of the native heart, stimuli-responsive biomaterials have also been used to engineer dynamic culture systems to understand how cardiac cells and tissues respond to progressive changes in extracellular microenvironments, enabling the investigation of dynamic cell mechanobiology. Here, we provide an overview of stimuli-responsive biomaterials used in cardiovascular research applications, with a specific focus on cardiac tissue engineering and dynamic cell mechanobiology. We also discuss how these smart materials can be utilized to mimic the dynamic microenvironment during heart development, which might provide an opportunity to reveal the fundamental mechanisms of cardiomyogenesis and cardiac maturation. 

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4. Three-dimensional scaffold-free microtissues engineered for cardiac repair

   https://doi.org/10.1039/D0TB01528H  

   Patino-Guerrero, Alejandra; Veldhuizen, Jaimeson; Zhu, Wuqiang; Migrino, Raymond Q.; Nikkhah, Mehdi (July 2020, Journal of materials chemistry)

   Cardiovascular diseases, including myocardial infarction (MI), persist as the leading cause of mortality and morbidity worldwide. The limited regenerative capacity of the myocardium presents significant challenges specifically for the treatment of MI and, subsequently, heart failure (HF). Traditional therapeutic approaches mainly rely on limiting the induced damage or the stress on the remaining viable myocardium through pharmacological regulation of remodeling mechanisms, rather than replacement or regeneration of the injured tissue. The emerging alternative regenerative medicine-based approaches have focused on restoring the damaged myocardial tissue with newly engineered functional and bioinspired tissue units. Cardiac regenerative medicine approaches can be broadly categorized into three groups: cell-based therapies, scaffold-based cardiac tissue engineering, and scaffold-free cardiac tissue engineering. Despite significant advancements, however, the clinical translation of these approaches has been critically hindered by two key obstacles for successful structural and functional replacement of the damaged myocardium, namely: poor engraftment of engineered tissue into the damaged cardiac muscle and weak electromechanical coupling of transplanted cells with the native tissue. To that end, the integration of micro- and nanoscale technologies along with recent advancements in stem cell technologies have opened new avenues for engineering of structurally mature and highly functional scaffold-based (SB-CMTs) and scaffold-free cardiac microtissues (SF-CMTs) with enhanced cellular organization and electromechanical coupling for the treatment of MI and HF. In this review article, we will present the state-of-the-art approaches and recent advancements in the engineering of SF-CMTs for myocardial repair. 

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5. Cardiac inducing RNAs (CIRs) from human fetal heart promote the differentiation of non-muscle cells to form into cardiomyocytes in vitro.

   https://doi.org/10.31031/AICS.2021.03.000553  

   Lemanski, L.F. (April 2021, Advancements in case studies)

   null (Ed.)

   We have discovered a cardiac-inducing RNA (CIR) in the axolotl, Ambystoma mexicanum, (a salamander) and two cardiac inducing RNAs (CIR-6 and CIR-30) in human heart that have the ability to induce the differentiation of non-muscle cells, including induced pluripotent stem cells from human skin, mouse embryonic stem cells, and mouse fibroblasts into cardiomyocytes in vitro. Although the primary sequences of salamander and human RNAs are not homologous, their secondary structures are very similar and we believe account for their shared unique abilities to promote differentiation of non-muscle cells into definitive cardiomyocytes. We are beginning to explore the potential for repair/regeneration of cardiac muscle in vivo using mouse and rat models with induced acute myocardial infarctions (AMI) to determine if pluripotent stem cells or fibroblasts transfected with the human CIRs or CIRs alone injected into the damaged areas of the hearts can effect repair of the damaged cardiac muscle tissue, and return the infarcted hearts and the AMI animal models to pre-heart-attack function again. If cardiac cells damaged in heart attacks can be replaced with living, functioning cardiomyocytes, patients with heart disease would be able to have normal heart function restored and could return to normal pre-heart-attack activity levels. Understanding how CIR transforms non-muscle cells into vigorously contracting, functional cardiac muscle and effectively replacing damaged heart cells with newly-formed cardiac muscle tissue would represent a major breakthrough in modern biology and medicine with the potential to have a significant impact on the survival rate and quality of life of millions of individuals worldwide who suffer heart attacks each year. 

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