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Review

Telocytes in cardiac regeneration and repair Yihua Bei a,b , Qiulian Zhou a , Qi Sun a , Junjie Xiao a,b,∗ a b

Regeneration and Aging Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China Shanghai Key Laboratory of Bio-Energy Crops, School of Life Science, Shanghai University, Shanghai 200444, China

a r t i c l e

i n f o

Article history: Received 16 January 2016 Accepted 24 January 2016 Available online xxx Keywords: Telocytes Regeneration Cardiomyocytes Stem cells Progenitor cells Exosomes

a b s t r a c t Telocytes (TCs) are a novel type of stromal cells reported by Popescu’s group in 2010. The unique feature that distinguishes TCs from other “classical” stromal cells is their extremely long and thin telopodes (Tps). As evidenced by electron microscopy, TCs are widely distributed in almost all tissues and organs. TCs contribute to form a three-dimensional interstitial network and play as active regulators in intercellular communication via homocellular/heterocellular junctions or shed vesicles. Interestingly, increasing evidence suggests the potential role of TCs in regenerative medicine. Although the heart retains some limited endogenous regenerative capacity, cardiac regenerative and repair response is however insufficient to make up the loss of cardiomyocytes upon injury. Developing novel strategies to increase cardiomyocyte renewal and repair is of great importance for the treatment of cardiac diseases. In this review, we focus on the role of TCs in cardiac regeneration and repair. We particularly describe the intercellular communication between TCs and cardiomyocytes, stem/progenitor cells, endothelial cells, and fibroblasts. Also, we discuss the current knowledge about TCs in cardiac repair after myocardial injury, as well as their potential roles in cardiac development and aging. TC-based therapy or TC-derived exosome delivery might be used as novel therapeutic strategies to promote cardiac regeneration and repair. © 2016 Elsevier Ltd. All rights reserved.

Contents 1. 2.

3. 4.

5. 6. 7. 8.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 General aspects of telocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.1. Morphology and immunophenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Cellular junctions of telocytes with other types of cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 2.2. 2.3. Potential roles of telocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Telocyte identification in the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Heterocellular communication of cardiac telocytes: cell basis for regenerative medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Telocyte-cardiomyocyte connection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Telocyte-cardiac stem/progenitor cell connection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.3. Telocyte-other interstitial cell connection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Telocytes in myocardial infarction and heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Telocytes in cardiac development and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Telocyte-derived exosomes in cardiac regeneration and repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author at: Regeneration and Aging Lab, Experimental Center of Life Sciences, School of Life Science, Shanghai University, Shanghai 200444, China. Fax: +86 21 66138131. E-mail address: [email protected] (J. Xiao). http://dx.doi.org/10.1016/j.semcdb.2016.01.037 1084-9521/© 2016 Elsevier Ltd. All rights reserved.

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1. Introduction Telocytes (TCs) are a novel type of stromal cells reported by Popescu’s group as a case of serendipity in 2010 [1]. The unique morphological feature of TCs which distinguishes them from “classical” stromal cells is their extremely thin and long telopodes (Tps) [2]. Additionally, TCs are completely different from other stromal cells according to their distinctive immunophenotypes, gene expressions, proteomics, and microRNA profiles [3–9]. As evidenced by transmission electron microscopy and electron tomography, TCs were found to be widely distributed in almost all organs and tissues including heart [10]. Recently, the focused ion beam scanning electron microscopy (FIB-SEM) tomography further provides a three-dimensional (3D) reconstruction and a spatial view of human cardiac and skin TCs [11,12]. Based on their long and dichotomous Tps, TCs contribute to establish a 3D interstitial network and participate in the intercellular communication via homocellular and heterocellular junctions or shed vesicles [13]. Meanwhile, TCs were indicated to be involved in tissue homeostasis, development, and immunosurveillance [10]. The number, distribution, and ultrastructural changes of TCs were also reported in many pathologies and diseases [14–21]. Interestingly, increasing evidence suggests that TCs might play an important role in tissue regeneration and repair [22]. TCs have their strategic location in the stem cell niches of different organs and tissues. They are supposed to support the homeostasis of stem cell niche, to guide or nurse the stem/progenitor cells, and also to influence their survival and activity. Particularly, TCs were reported to be reduced in myocardial infarction (MI), while intramyocardial delivery of cardiac TCs was protective against myocardial injury [23,24]. The heart retains an endogenous but weak regenerative capacity, which is obviously not enough to make up the loss of cardiomyocytes in response to myocardial injury [25,26]. Thus, developing novel strategies to increase cardiomyocyte renewal and repair is of great importance for the treatment of cardiac diseases [27,28]. This review focuses on the potential role of TCs in cardiac regeneration and repair. We first introduce the general aspects of TCs, including their morphology, immunophenotype, cellular junctions, and potential functions. We then describe the distribution of cardiac TCs and their communication with surrounding cells (cardiomyocytes, stem/progenitor cells, endothelial cells, and fibroblasts), particularly in terms of cell basis for cardiac regeneration. We further discuss the involvement of TCs in cardiac repair after myocardial injury, and their potential roles in cardiac development and aging. Finally, we suggest TC-derived exosomes as a novel therapeutic target to promote cardiac regeneration and repair.

2. General aspects of telocytes 2.1. Morphology and immunophenotype The distinct morphology of TCs is characterized with a small cell body (9.39 ± 3.26 ␮m in diameter) and extremely thin (0.10 ± 0.05 ␮m in thickness) and long Tps (up to 1000 ␮m in length) [1]. The cell body contains a nucleus and a small amount of cytoplasm accommodating mitochondria, endoplasmic reticulum, Golgi complex, and cytoskeletal elements [29,30]. Tps have dichotomous and moniliform aspects, which are featured by alternate thin segments (podomers) and dilated segments (podoms). Moreover, multiple functional cell organelles including mitochondria and endoplasmic reticulum, as well as caveolae could be found at the level of dilations [31]. Tps could form a labyrinthine network in the interstitial space, which indeed facilitates intercellular communication between TCs and other cells [32–34]. To date, the

electron microscopy is still the unique golden standard method to identify TCs, which provides evidence for the widely distribution of TCs in almost all organs including heart [35–37]. The double immunolabellings for CD34 and CD117 (c-kit), vimentin, platelet-derived growth factor receptor (PDGFR)-␣, or PDGFR-␤ help distinguish TCs from other cells [38–40]. Despite the fact that no specific immunophenotype for TCs has yet been identified, the immunolabellings for TCs remain a useful tool to make semi-quantitative analysis for TCs [18,41]. It has been reported that the PDGFR-␣ positive but CD34 negative TCs are located in the suburothelium, while the PDGFR-␣ negative but CD34 positive ones are present in the submucosa and detrusor of human urinary bladder [42]. Thus, TC immunophenotype could be varied in different types of organs and tissues [43–45]. Moreover, TCs could undergo immunophenotype changes as evidenced by a gradual gain of CD34 phenotype during cardiac development, which was however initially negative in embryo [2]. 2.2. Cellular junctions of telocytes with other types of cells With the advance of transmission electron microscopy and electron tomography, it has been revealed that TCs, especially with their long and dichotomous Tps, can form both homocellular and heterocellular junctions with neighboring cells, vessels, and nerve endings [13,46,47]. In addition to the connect with parenchyma cells (e.g., cardiomyocytes, alveolar epithelial cells, skeletal muscle cells, and hepatocytes), TCs form cellular junctions with other stromal cells and interstitial elements such as fibroblasts, pericytes, and collagen/elastic fibers [38,48,49]. Particularly, connections between TCs and immunoreactive cells like macrophages, mast cells, and eosinophils are called “stromal synapses” [21,50]. Moreover, TCs have been identified in stem cell niches of different tissues and organs, proposing its potential role in tissue regeneration and repair [40,50–53]. Different junction types including point contact, electron-dense nanostructure, and planar contact are usually found connecting TCs with other cells, facilitating intercellular signaling via direct connection [13]. Meanwhile, narrow spaces are also present between the cell membranes of TCs and neighboring cells, suggesting the indirect cellular communication via small molecules or shed vesicles (e.g., exosomes) [36,54,55]. With the currently most advanced electron microscope technology (FIB-SEM), the 3D reconstruction of human cardiac and skin TCs were realized, allowing a vivid view and better understanding of TCs in intercellular signaling and communication [11,12]. 2.3. Potential roles of telocytes Due to the unique morphological features and intercellular communication with other cells, multiple functions have been proposed for TCs. TCs contribute to establish a 3D interstitial network, assuring mechanical support and tissue homeostasis [49,56,57]. The presence of TCs in close vicinity of mature or progenitor cardiomyocytes in the myocardium samples of embryonic (E14 and E17) mice suggest a role of TCs in cardiac development [58]. TCs are also considered as important regulators in immunomodulation and immunosurveillance [3,14]. Moreover, TCs might be involved in a variety of pathology, including cholelithiasis [17], inflammatory bowel diseases [19,59], cancers [20], liver fibrosis [18], systemic sclerosis [16,60], and psoriasis [21]. Besides that, much attention has been attracted for the crucial role of TCs in regenerative medicine [22]. TCs have strategic locations in stem cell niches within a variety of tissues and organs such as heart [13], lungs [51], liver [49], skeletal muscle [48], skin [50], eye [61], and meninges and choroid plexus [40]. It has been supposed that TCs might function as guidance and nurse devices for stem and progenitor cells,

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and also contribute to the activation, proliferation, and differentiation of stem cells during tissue regeneration and repair [22]. 3. 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 are widely distributed in the epicardium [53,62], myocardium [63], endocardium [64], and even cardiac valves [65], as evidenced by electron microscopy. TCs make a supportive interstitial network and act 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 [13]. In adult hearts, TCs have CD34, c-kit, vimentin, and PDGFR-␤ immunophenotypes [54,58,62,66]. It has recently been demonstrated that cardiac TCs also express CD34/PDGFR-␣ [67], although the latter was previously considered as a specific marker for TCs in gastrointestinal system [68]. In primary culture, the TC proliferative ability and dynamics of Tp extension depend on the culture condition and matrix proteins [69,70]. Cardiac TCs are easily to be distinguished from fibroblasts, pericytes, and bone mesenchymal stem cells (BMSC) due to different immunophenotypes [66,71]. The CD34/c-kit cardiac TCs have lower telomerase activity than BMSC, cardiac fibroblasts, and cardiomyocytes [69]. Analyzed with isobaric tag for relative and absolute quantification (iTRAQ) and automated 2-D nano-ESI LC–MS/MS, the protein profiles of cardiac TCs were found to be different from endothelial cells [9]. In addition, miR-193 has been reported to be differentially expressed by TCs and other stromal cells [8]. 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 [72]. 4. Heterocellular communication of cardiac telocytes: cell basis for regenerative medicine 4.1. Telocyte-cardiomyocyte connection With the electron microscopy, the direct connections TCscardiomyocytes could be easily found within the heart and even in primary culture or engineered heart tissue [13,54]. The dot contacts and small electron-dense nanostructures are common junctions between TCs and cardiomyocytes [13]. The electron tomography revealed that the nanocontacts (10–15 nm) or even more complex and atypical junctions (e.g., molecular interactions) existed between TCs and cardiomyocytes [33]. In primary culture of TCs from neonatal rat cardiac tissues, TCs extend their Tps to the surrounding cardiomyocytes, which might contribute to the synchronous beating of cardiac cells [54]. Moreover, the direct connections or shed vesicles between TCs and cardiomyocytes in the 3D engineered heart tissue strongly support the concept that TCs play a vital role in the architectural organization of the heart [73]. Noteworthy, the cardiac TC-released extracellular vesicles (e.g., exosomes, ectosomes, and multivesicular cargos) are important transporters for biological signalings between TCs and cardiomyocytes [36]. Adult cardiomyocytes retain a limited endogenous proliferative ability in response to specific stimuli [25,26]. This potential, although limited, represents an important cell basis for heart regeneration and repair. Importantly, exercise has been proven as a physiological stimulus for cardiac growth, with both hypertrophy and proliferation of cardiomyocytes [74]. The IGF-1/PI3 K/Akt

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signaling and the C/EBP␤/Cited4 transcription factor are key regulators for exercise-induced cardiac growth [75]. In addition, miR-222 has been reported to be essential for physiological cardiac growth, and miR-222 overexpression attenuates cardiac remodeling after ischemia-reperfusion injury (IRI) [76]. These data suggest exercise as a useful tool to prevent and treat cardiac diseases [27]. In this regard, the TC-cardiomyocyte interaction deserves further exploration in exercise-induced cardiac growth as well as in cardiac pathological conditions. 4.2. Telocyte-cardiac stem/progenitor cell connection The stem cell therapy has been increasingly considered as a novel strategy to promote cardiac regeneration and repair in ischemic heart diseases [77–79]. Different from embryonic stem cells (ethical concerns and immunogenic and tumorigenic problems), resident stem cells may represent appropriate and safe candidates for stem cell therapy [80]. The epicardium was identified as a novel source of putative cardiac stem cells (CPCs) and cardiomyocyte progenitors (CMPs) [81]. Interestingly, TCs are undoubtedly distributed in epicardial stem cell niche, in close vicinity of clusters of CPCs and CMPs [53]. As evidenced by electron microscopy and electron tomography, the “stromal synapses” (with electron-dense nanostructures), as well as adhaerens junctions, are found to be present between TCs and CSCs in tissue [13]. TCs are supposed to support the homeostasis of stem cell niche and to regulate stem cell fate (proliferation, activation, and differentiation) and heart regeneration. Moreover, both the epicardium-derived cells (EPDCs) and TCs express c-kit and PDGFR-␤, suggesting that cardiac TCs might be a subpopulation of EPDCs [82]. Similarly, the “stromal synapses” or adhaerens junctions also exist between TCs and CSCs in culture [83]. It has previously been indicated that the adhaerens junctions between stem cells and other stromal cells not only control the retention of stem cell niche, but also regulate the division of stem cells [84]. Interestingly, the CSCs in the presence of TCs displayed higher division property in co-culture system, further indicating the role of TCs in CSC proliferation [83]. In addition, the “stromal synapses” (intercellular distances within 15–100 nm) suppose the molecular interaction between TCs and CSCs [83]. Using the Cy5-miR-21 oligos and calcein-labelled extracellular vesicles, it was revealed that cardiac TCs and CSCs could shuttle microRNA via a bidirectional vesicular signaling mechanism [55]. Recently, the effect of cardiac TC secretome on CSC fate has been assessed in vitro [85]. A higher level of IL-6, vascular endothelial growth factor (VEGF), macrophage inflammatory protein-1␣ (MIP1␣), MIP-2, MCP-1, and some chemokines was identified in the supernatant of cardiac TCs compared to CSCs. Moreover, the coculture of cardiac TCs and CSCs resulted in further increased MIP-1␣ and MIP-2 level, while reduced IL-2 level compared with TC or CSC mono-culture, indicating a cellular interaction via paracrine effects [85]. It has been supposed that the increased TC secretome (IL-6, IL-6-type cytokines, and VEGF) might affect the proliferation and differentiation of CSCs, and control the angiogenesis during heart regeneration [86–88]. To date, the clinical results of stem cell therapy are still far from ideal due to poor stem cell integration, survival, and in situ activity [89]. In light of these considerations, the cardiac TCs, via either direct contacts or paracrine mechanisms, may synergistically act with CSCs to promote heart regeneration and repair. 4.3. Telocyte-other interstitial cell connection Although TCs represent only about 1% of interstitial cells in the human heart, they contribute to form a complex 3D network by interacting with surrounding stromal cells, including endothe-

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lial cells, pericytes, fibroblasts, macrophages, and Schwann cells [13,90]. There are point and/or planar contacts between cardiac TCs and these cells [13]. Increasing evidence suggests that, in addition to cardiomyocytes, non-cardiomyocytes are also active regulators for cardiac regeneration [91]. The endothelial cells, with regulation of VEGF and endothelial nitric oxide synthase (eNOS), are key players in neo-angiogenesis and endothelial function, which are considered as important components for cardiac repair after ischemic injury [92,93]. It was reported that TCs, in tandem with endothelial cells of preexisting or neo-formed capillaries, were increased in the border zone of infarcted myocardium during angiogenesis process, suggesting a role of TCs in neo-vascularization after MI [22]. The cardiac fibroblast activation and transdifferentiation account for the production and accumulation of extracellular matrix, leading to the development of cardiac fibrosis and pathological cardiac remodeling [94]. Actually, decreased number of TCs have been found in the fibrotic changes in systemic sclerosis [16,60], inflammatory bowel diseases [19,59], liver fibrosis [18], and also MI [23,24], suggesting a potential relationship between TCs and fibroblasts. Based on the direct contact and/or paracrine signaling between TCs and fibroblasts, TCs are supposed to regulate the fibroblast/myofibroblast activity, thus affecting fibrosis [16,18,60]. In this regard, further investigation is highly needed to clarify the potential role of TCs in cardiac fibrosis and pathological remodeling.

5. Telocytes in myocardial infarction and heart failure Myocardial infarction (MI) is a major cause of death and disability worldwide [95]. 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 [96]. In a rat experimental myocardial infarction model, TCs were found to be significantly increased in the border zone of infarction in the angiogenesis process (30 days after MI) compared to normal myocardium [97]. Based on transmission electron microscopy, the direct nanocontacts, as well as the shed vesicles, were detected between TCs and the abluminal face of endothelium of neo-formed or preexisting capillaries [97]. Moreover, cardiac TCs secret VEGF and NOS2, and express angiogenic microRNAs (e.g., let-7e, 10a, 21, 27b, 100, 126-3p, 130a, 143, 155, and 503), further suggesting a role of cardiac TCs in angiogenesis process after MI [97]. As evidenced by immunofluorescent staining and semiquantification of TCs, cardiac TCs were decreased and undetectable in the infarct zone at 4 days after MI [23]. In the border zone, cardiac TCs were also reduced but slightly increased by 14 days after MI [23]. 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 [23,24]. Meanwhile, the enhanced angiogenesis was also detected in TC-transplanted myocardium at 14 weeks after MI [24]. Thus, increasing cardiac TCs gives rise to protective effect against MI, whereby they are supposed to enhance angiogenesis and reduce cardiac fibrosis [24,97]. Also, cardiac TCs contribute to rebuild cardiac interstitial network and maintain the function of the myocardium, which might also be important to provide appropriate microenvironment for the migration and development of cardiac stem/progenitor cells [83,85]. 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 [98–100]. 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 [101]. Although the infarct size was not significantly different between iMSC-injected and saline-injected animals, there was a higher vascular density and increased TC distribution in iMSC-injected hearts, compared to saline-injected animals or sham-operated animals [101]. Similarly, the intramyocardial injection of iPSC-derived human cardiac progenitor cells (CPCs) was also associated with improved ventricular remodeling, enhanced neovascularization, and increased cardiac TC populations (especially in the infarct zone) at 4 weeks after MI, compared to cardiomyocyteinjected or saline-injected animals [102]. Interestingly, several CD34-positive cardiac TCs were found to be immunoreactive to human-specific Ku80, indicating the presence of both endogenous (CD34 positive only) and exogenous (both CD34 and Ku80 positive) TCs in iMSC-injected or cardiac progenitor-injected hearts [101,102]. Due to the fact that no notable differentiation of transplanted iMSCs or CPCs toward cardiomyocytes was detected in the infarct myocardium, the benefit of cell transplantation in MI might be closely related to a paracrine mechanism [103,104]. Moreover, the increased population of cardiac TCs with stem cell therapy further indicates the potential interstitial cell interactions in the infarcted myocardium [101,102]. Heart failure is a common end-stage of many cardiovascular diseases [105]. The role of TCs in heart failure has recently been investigated in patients with dilated, ischemic, or inflammatory cardiomyopathy-associated heart failure [106]. The c-kit immunolabelling revealed that TCs and Tps were decreased in the failing human myocardium, and even absent in severe collagen deposition areas. The diminished TCs were associated with increased apoptosis as evidenced by transmission electron microscopy and Tunel staining. Moreover, the number of TCs in the myocardium was inversely correlated with the amount of collagen type I, while higher degraded collagens were associated with reduced TCs, indicating that the composition of extracellular matrix might affect the number and distribution of cardiac TCs [106]. It remains to further clarify the impact of diminished and ultrastructurally damaged TCs on the 3D interstitial organization, the intercellular communication, and the maintenance of cardiac stem cell niche in the failing myocardium [10]. For better understanding, the potential mechanisms responsible for the protective effects of TCs against myocardial injury (e.g., myocardial infarction) are illustrated in Fig. 1 .

6. Telocytes in cardiac development and aging It is 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 [107,108]. Being considered as a subpopulation of EPDCs, TCs were found to be constantly present in the embryonic, newborn, and adult mice hearts [109]. 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-kit immunoreactivity of cardiac TCs decreased along with cell differentiation [109]. 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 [109]. The in vitro time-lapse videomicroscopy further provided evidence that cardiac TCs might guide and control the aggregation of immature cardiomyocytes [109]. In light of these

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Fig. 1. Potential mechanisms involved in the protective effects of telocytes (TCs) against myocardial infarction (MI). TCs, either via direct contacts or shed vesicles (e.g., exosomes), are supposed to influence the surrounding cells, including cardiomyocytes, stem/progenitor cells, endothelial cells, and fibroblasts, thus leading to improved cardiomyocyte renewal and neovascularization and reduced fibrosis in injured myocardium.

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 [58,110]. The limited regenerative potential of the adult heart is unfortunately further hampered with aging process, thus causing increased risk factors for cardiovascular diseases and the rising incidence of heart failure [111,112]. The aged myocardium suffers sustained oxidative stress and mitochondrial damage, leading to cardiomyocyte apoptosis and necrosis, accumulation of extracellular matrix, and increased angiogenesis [113–117]. Numerically, TCs and CSCs were significantly decreased in the adult heart versus newborn heart [90]. 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 regenerative and repair capacity of the aging heart [90]. 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 aging process. 7. Telocyte-derived exosomes in cardiac regeneration and repair Transmission electron microscopy and electron tomography provide direct evidence that cardiac TCs can secret extracellular vesicles, which serve as important transporters for biological signalings between cells [13,62]. Cardiac TCs release three types of extracellular vesicles: exosomes (45 ± 8 nm), ectosomes (128 ± 28 nm), and multivesicular cargos (1 ± 0.4 ␮m), depending on their mechanisms of biogenesis and secretion [36]. Extracellular vesicles can carry a variety of molecules, including lipids, proteins, DNA, mRNA, and non-coding RNA, thus also acting as vehicles for genetic information exchanges between cells [118]. Growing evidence suggests that exosomes play an important role in the cross talk of different intramyocardial cells, contributing to cardiac physiology and responses to injury [119]. Interestingly, intramyocardial delivery of ESC-, MSC-, iPSC-, or CPC-derived exosomes

were associated with reduced myocardial apoptosis and fibrosis, enhanced neovascularization, and improved cardiac function after experimental MI [120–123]. The enriched exosomal angiogenic or anti-apoptotic microRNAs (e.g., miR-21, miR-210, miR-132, and miR-146a-3p) were thought to be responsible for the cardioprotective effects of exosomes [120,121]. As described above, increased cardiac TCs were detected in the angiogenic areas of MI border zone, with the presence of secreted exosomes around their cell bodies and Tps [97]. These exosomes were supposed to contain a cocktail of biological information (e.g., microRNAs), thus regulating the neighboring cells like endothelial cells and promoting angiogenesis via a paracrine mechanism [97]. Moreover, the in vitro studies provide strong evidence that cardiac TCs could also regulate the CSC activity via exosomes [55,85]. Given that the intramyocardial injection of cardiac TCs was effective to reduce the infarct size and myocardial fibrosis in experimental MI, further studies are needed to evaluate the functional role of TC-secreted exosomes in cardiac responses to injury [23,24]. Moreover, TC-derived exosomes could also be used as novel therapeutic nanoparticles that promote cardiomyocyte survival, neovascularization, and stem/progenitor cell activation in cardiac regeneration and repair [124,125]. 8. Future directions Increasing evidence shows the vital roles of TCs in cardiac homeostasis and adaptive responses of the heart to injury. Importantly, TCs are considered as critical contributors to cardiac regeneration and repair. However, direct evidence of the functional impact of cardiac TCs on cardiomyocytes and non-myocytes (e.g., endothelial cells, fibroblasts, and stem/progenitor cells) is still lacking. Meanwhile, the intercellular signaling and communication mechanism between TCs and other cells, either via direct contacts or shed vesicles, remains a topic for further investigation. Also, it will be of great interest to clarify the role of TCs in exercise-induced physiological cardiac growth as well as in aging-related myocar-

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dial dysfunction. Overall, TC-based therapy or TC-derived exosome delivery might be novel strategies to promote cardiac regeneration and repair. Conflicts of interest The authors declare there are no conflicts of interest. Acknowledgments This work was supported by the grants from National Natural Science Foundation of China (81570362 and 81200169 to JJ Xiao, and 81400647 to Y Bei), Innovation Program of Shanghai Municipal Education Commission (13YZ014 to JJ Xiao), Innovation fund from Shanghai University (sdcx2012038 to JJ Xiao) and Program for the integration of production, teaching and research for University Teachers supported by Shanghai Municipal Education Commission (year 2014, to JJ Xiao). References [1] L.M. Popescu, M.-S. Faussone-Pellegrini, Telocytes—a case of serendipity: the winding way from interstitial cells of cajal (ICC), via interstitial cajal-like cells (ICLC) to telocytes, J. Cell. Mol. Med. 14 (April) (2010) 729–740. [2] M.-S.F. Pellegrini, L.M. Popescu, Telocytes, Biomol. Concepts 2 (2011) 481–489. [3] X. Sun, M. Zheng, M. Zhang, M. Qian, Y. Zheng, M. Li, et al., Differences in the expression of chromosome 1 genes between lung telocytes and other cells: mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells and lymphocytes, J. Cell. Mol. Med. 18 (May) (2014) 801–810. [4] M. Zheng, X. Sun, M. Zhang, M. Qian, Y. Zheng, M. Li, et al., Variations of chromosomes 2 and 3 gene expression profiles among pulmonary telocytes, pneumocytes, airway cells, mesenchymal stem cells and lymphocytes, J. Cell. Mol. Med. 18 (October) (2014) 2044–2060. [5] Y. Zhu, M. Zheng, D. Song, L. Ye, X. Wang, Global comparison of chromosome X genes of pulmonary telocytes with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes, J. Transl. Med. 13 (September) (2015) 318. [6] J. Wang, L. Ye, M. Jin, X. Wang, Global analyses of chromosome 17 and 18 genes of lung telocytes compared with mesenchymal stem cells, fibroblasts, alveolar type II cells, airway epithelial cells, and lymphocytes, Biol. Direct 10 (2015) 9. [7] D. Song, D. Cretoiu, M. Zheng, M. Qian, M. Zhang, S.M. Cretoiu, et al., Comparison of chromosome 4 gene expression profile between lung telocytes and other local cell types, J. Cell. Mol. Med. (December) (2015), http://dx.doi.org/10.1111/jcmm.12746. [8] V.B. Cismasiu, E. Radu, L.M. Popescu, miR-193 expression differentiates telocytes from other stromal cells, J. Cell. Mol. Med. 15 (May) (2011) 1071–1074. [9] Y. Zheng, D. Cretoiu, G. Yan, S.M. Cretoiu, L.M. Popescu, H. Fang, et al., Protein profiling of human lung telocytes and microvascular endothelial cells using iTRAQ quantitative proteomics, J. Cell. Mol. Med. 18 (June) (2014) 1035–1059. [10] S.M. Cretoiu, L.M. Popescu, Telocytes revisited, Biomol. Concepts 5 (October) (2014) 353–369. [11] D. Cretoiu, M. Gherghiceanu, E. Hummel, H. Zimmermann, O. Simionescu, L.M. Popescu, FIB-SEM tomography of human skin telocytes and their extracellular vesicles, J. Cell. Mol. Med. 19 (April) (2015) 714–722. [12] D. Cretoiu, E. Hummel, H. Zimmermann, M. Gherghiceanu, L.M. Popescu, Human cardiac telocytes: 3D imaging by FIB-SEM tomography, J. Cell. Mol. Med. 18 (November) (2014) 2157–2164. [13] M. Gherghiceanu, L.M. Popescu, Cardiac telocytes—their junctions and functional implications, Cell Tissue Res. 348 (May) (2012) 265–279. [14] Y. Zheng, C. Bai, X. Wang, Telocyte morphologies and potential roles in diseases, J. Cell. Physiol. 227 (June) (2012) 2311–2317. [15] Y. Zheng, C. Bai, X. Wang, Potential significance of telocytes in the pathogenesis of lung diseases, Expert Rev. Respir. Med. 6 (February) (2012) 45–49. [16] M. Manetti, S. Guiducci, M. Ruffo, I. Rosa, M.S. Faussone-Pellegrini, M. Matucci-Cerinic, et al., Evidence for progressive reduction and loss of telocytes in the dermal cellular network of systemic sclerosis, J. Cell. Mol. Med. 17 (April) (2013) 482–496. [17] A. Matyja, K. Gil, A. Pasternak, K. Sztefko, M. Gajda, K.A. Tomaszewski, et al., Telocytes: new insight into the pathogenesis of gallstone disease, J. Cell. Mol. Med. 17 (June) (2013) 734–742. [18] S. Fu, F. Wang, Y. Cao, Q. Huang, J. Xiao, C. Yang, et al., Telocytes in human liver fibrosis, J. Cell. Mol. Med. (February) (2015), http://dx.doi.org/10.1111/ jcmm.12542.

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