Telocytes in cardiac regeneration and repair
Telocyte identification in the heart
Since the discovery of TCs in 2010, the scientists have been increasing their focus on the functional roles of TCs in the heart. TCS is widely distributed in the epicardium, myocardium, endocardium, and even cardiac valves, as evidenced by electron microscopy. TCS makes a supportive interstitial network and acts as important regulators in intercellular signaling with the surrounding cells (cardiomyocytes, stem/progenitor cells, endothelial cells, pericytes, fibroblasts, and immunoreactive cells), blood vessels, nerve endings, and extracellular matrix elements. In adult hearts, TCs have CD34, c-kit, vimentin, immunophenotypes. It has recently been demonstrated that cardiac TCs also express CD34/PDGFR, although the latter was previously considered as a specific marker for TCs in
the gastrointestinal system. In primary culture, the TC proliferative ability and dynamics of Tp extension depend on the culture condition and matrix proteins. Cardiac TCs are easy to be distinguished from fibroblasts, pericytes, and bone mesenchymal stem cells (BMSC) due to different immunophenotypes. The CD34/c-kit cardiac TCs have lower telomerase activity than BMSC, cardiac fibroblasts, and cardiomyocytes. Analyzed with an isobaric tag for relative and absolute quantification (Iraq) and automated 2-D nano-ESI LC-MS/MS, the protein profiles of cardiac TCs were found to be different from endothelial cells. In addition, miR-193 has been reported to be differentially expressed by TCs and other stromal cells. These findings highly confirm cardiac TCs as a unique cell population. Noteworthy, cardiac TCs in primary culture positively express embryonic stem cell marker Nanog and myocardial stem cell marker Sca-1, indicative of pluripotent properties of TCs.
Telocytes in myocardial infarction and heart failure
Myocardial infarction (MI) is a major cause of death and disability worldwide. The ischemic myocardium suffers a loss of cardiomyocytes via necrosis and apoptosis, and undergoes neoangiogenesis and fibrotic changes, leading to pathological cardiac remodeling and probably end-stage heart failure. In a rat experimental myocardial infarction model, TCs were found to be significantly increased in the border zone of infarction in the angiogenesis process (30days afterMI) compare to dtonormalmyo Cardium. Based on transmission electron microscopy, the direct nanocontacts, as well as the shed vesicles, were detected between TCs and the abluminal face of the endothelium of neo-formed or preexisting capillaries. Moreover, cardiac TCs secret VEGF and NOS2, and express angiogenic microRNAs (e.g., let-7e, 10a, 21, 27b, 100, 126-3p, 130a, 143, 155, and503),further suggesting a role of cardiac TCs in angiogenesis process after MI. As evidenced by immunofluorescent staining and semi quantification of TCs, cardiac TCs were decreased and undetectable in the infarct zone at 4 days after MI. In the border zone, cardiac TCs were also reduced but slightly increased by 14 days after MI. Interestingly, intramyocardial transplantation of cardiac
TCS was proved to be effective to alleviate MI both at 14 days and 14 weeks after coronary ligation, with improved cardiac function and reduced infarct size and cardiac fibrosis. Meanwhile, the enhanced angiogenesis was also detected in TC-transplanted myocardium at 14 weeks after MI. Thus, increasing cardiac TCs gives rise to a protective effect against MI, whereby they are supposed to enhance angiogenesis and reduce cardiac fibrosis. Also, cardiac TCs contribute to rebuild the cardiac interstitial network and maintain the function of the myocardium, which might also be important to provide an appropriate microenvironment for the migration and development of cardiac stem/progenitor cells. The induced pluripotent stem cells (iPSCs) offer a better solution in terms of cell population size and have properties of differentiation similar to embryonic stem cells (ESCs), which are considered as a novel source of cell therapy for MI. The intramyocardial injection of iPSC-derived human mesenchymal stem cells (MSCs) was demonstrated to prevent ventricular remodeling with restricted ventricular dilation and improved myocardial radial strain at 8 weeks after MI, as evidenced by segmental speckle tracking analysis.
Telocytes in cardiac development and aging
Itis generally accepted that the cardiac epicardium-derived cells (EPDCs) play important roles in cardiac development, which could differentiate into smooth muscle cells, fibroblasts, and endothelial cells, and also participate in the form of subepicardial mesenchyme, blood vessels, atrioventricular valves, and Purkinje fibers. Being considered as a subpopulation of EPDCs, TCs were found to be constantly present in the embryonic, newborn, and adult mice hearts. With sustained immunoreactivity to vimentin, cardiac TCs were initially CD34 negative (Embryonic 14), but gradually CD34 positive from late embryonic (Embryonic 17) to adult life. On the other hand, the c-kitimmunoreactivity of cardiac TCs decreased along with cell differentiation. As evidenced by transmission electron microscopy, TCs were widely distributed in the subepicardial layer, embracing the surrounding growing cardiomyocytes and endothelial cells via Tps or interacting with these cells via releasing exosomes. The in vitro time-lapse videomicroscopy further provided evidence that cardiac TCs might guide and control the aggregation of immature cardiomyocytes. In light of these findings, TCs might also be considered as a novel therapeutic target to enhance cardiomyocyte renewal under pathological conditions based on re-activated prenatal heart development. The limited regenerative potential of the adult heart is unfortunately further hampered with the aging process, thus causing increased risk factors for cardiovascular diseases and the rising incidence of heart failure. The aged myocardium suffers sustained oxidative stress and mitochondrial damage, leading to cardiomyocyte apoptosis and necrosis, accumulation of extracellular matrix, and increased angiogenesis. Numerically, TCs, and CSCs were significantly decreased in the adult heart versus newborn heart. Although cardiac TCs and stem cells represent only a small fraction of human cardiac interstitial cells (0.5–1% and 0.1–0.5%, respectively), their reduction could be very important reasons for diminished generative and repair capacity of the aging heart. In this regard, increasing cardiac TCs, together with their influence on the activity of CSCs, might be a novel approach to enhance cardiac regeneration and repair during the aging process.
Author: Yihua Bei, Qiulian Zhoua, Qi Suna, Junjie Xiao