MSC-Derived lncRNAs' Role in Cardiac Injury and Repair: Comparison
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Please note this is a comparison between Version 2 by Wendy Huang and Version 1 by Narasimman Gurusamy.

Cardiac injury, such as myocardial infarction and heart failure, remains a significant global health burden. The limited regenerative capacity of the adult heart poses a challenge for restoring its function after injury. Mesenchymal stem cells (MSCs) have emerged as promising candidates for cardiac regeneration due to their ability to differentiate into various cell types and secrete bioactive molecules. Attention has been given to noncoding RNAs derived from MSCs, particularly long noncoding RNAs (lncRNAs), and their potential role in cardiac injury and repair. LncRNAs are RNA molecules that do not encode proteins but play critical roles in gene regulation and cellular responses including cardiac repair and regeneration.

  • mesenchymal stem cells
  • noncoding RNA
  • long noncoding RNA
  • cardiac injury and repair
  • myocardial injury
  • myocardial infarction

1. Introduction

Cardiac injury, such as myocardial infarction and heart failure, remains a leading cause of mortality and morbidity worldwide [1]. The limited regenerative capacity of the adult mammalian heart poses a significant challenge for restoring its function after injury [2]. Therefore, understanding the underlying mechanisms of cardiac injury and repair is crucial for developing effective therapeutic strategies.
Cardiac injury typically occurs because of reduced blood supply, often due to the occlusion of a coronary artery, leading to ischemia and subsequent myocardial infarction [3]. Ischemic injury triggers a cascade of events, including inflammation, oxidative stress, cell death, and extracellular matrix remodeling, that contribute to tissue damage and functional impairment [2,4][2][4]. The heart possesses intrinsic mechanisms to initiate repair following injury. These processes involve the coordinated response of various cell types, signaling pathways, and extracellular matrix remodeling [5,6][5][6]. Upon injury, resident cardiac cells, such as cardiomyocytes, fibroblasts, and endothelial cells, undergo phenotypic changes and contribute to the repair process [5,7][5][7].
In recent years, mesenchymal stem cells (MSCs) have emerged as promising candidates for cardiac regeneration [8]. MSCs are multipotent stem cells with the capacity to differentiate into various cell types, including cardiomyocytes, endothelial cells, and smooth muscle cells. Additionally, MSCs exhibit immunomodulatory and paracrine effects, secreting a range of bioactive molecules that can modulate the cardiac microenvironment and promote tissue repair [9,10][9][10]. Recently, to further elucidate the mechanisms underlying the regenerative potential of MSCs in the context of cardiac injury and repair, attention has been given towards noncoding RNAs such as microRNAs (miRs) and long noncoding RNAs (lncRNAs). LncRNAs are a class of RNA molecules longer than 200 nucleotides that do not encode proteins but play critical roles in gene regulation and cellular processes. Emerging evidence suggests that MSC-derived lncRNAs may contribute to cardiac repair and regeneration by modulating key signaling pathways and cellular responses.

2. LncRNA-TARID Improves Cardiac Function

MSC-derived EVs have been shown to be beneficial in improving adverse myocardial remodeling and myocardial fibrosis in mouse models of myocardial infarction [68][11]. The LncRNA termed as TARID (Tcf21 antisense RNA inducing demethylation) is known to activate Tcf21 expression by inducing its promoter demethylation [85][12]. Tcf21, a basic helix-loop transcription factor for cardiovascular development, is a potential target for enhancing cardiac remodeling [86][13]. Zhu et al. [68][11] demonstrated that lncRNA-TARID-laden lipid nanoparticles increased Tcf21 expression, leading to improved cardiac function and histology in murine and porcine models of myocardial infarction.

3. LncRNA HAND2-AS1 Protects against Cardiomyocyte Injury

Hypoxia/reoxygenation (H/R) injury in H9c2 cells reduced the expression of lncRNA HAND2 antisense RNA 1 (HAND2-AS1) and induced the expression of miR-17-5p [69][14]. Previously, it was identified that the expression of miR-17-5p was elevated during myocardial injury and cardiomyocyte apoptosis [87][15]. Bone marrow-MSC-derived exosomes containing HAND2-AS1 improved cell viability, reduced apoptosis, controlled oxidative stress, and repressed inflammation, attenuating H/R-induced damage in H9c2 cells; however, HAND2-AS1 knockdown partially reversed the beneficial effects of exosomes, highlighting the significance of the HAND2-AS1/miR-17-5p axis in H/R-injured myocardial cells [69][14].

4. LncRNA A2M-AS1 Attenuates Myocardial Injury

LncRNA A2M antisense RNA 1 (A2M-AS1) was found to be lowly expressed in patients with acute myocardial infarction and in H/R-induced cardiomyocytes [71][16]. Exosomes derived from lncRNA A2M-AS1-transfected MSCs provided protective effects to H/R-induced cardiomyocytes [88][17]. The study suggested that exosomal delivery of lncRNA A2M-AS1 ameliorates H/R-induced cardiomyocyte apoptosis and oxidative stress by sponging miR-556-5p and increasing X-linked inhibitor of apoptosis protein (XIAP), providing insights into the pathogenesis of myocardial ischemia/reperfusion (I/R) injury [88][17].

5. Inhibition of LncRNA ZFAS1 Improves Myocardial Infarction

LncRNA zinc finger antisense 1 (ZFAS1) was shown to be an independent predictor of myocardial infarction [89][18] and to accelerate cardiomyocyte apoptosis in myocardial infarction in mice caused by calcium overload [90,91][19][20]. Xiao et al. [72][21] studied the role of lncRNA ZFAS1 in both in vitro and in vivo models of MI. Treatment with MSC-derived EVs improved cardiomyocyte viability; increased the expression of Von Willebrand factor and VEGF; and activated the Akt, Nrf2, and Heme oxygenase-1 pathways; however, overexpression of lncRNA ZFAS1 reversed these effects of MSC-derived EVs [72][21]. The studies suggest that the inhibition of ZFAS1 and activation of the Akt/Nrf2/Heme oxygenase-1 pathway by MSC-derived EVs could potentially improve myocardial infarction outcomes.

6. LncRNA Mir9-3hg Mitigates Cardiac Injury by Inhibiting Ferroptosis

Exosomes derived from bone marrow MSCs were shown to have high-level expression of the lncRNA MIR9-3 host gene (Mir9-3hg) and to promote cell proliferation while increasing glutathione levels and reducing reactive oxygen species and ferroptosis in cardiomyocytes subjected to H/R injury [73][22]. Additionally, it has been demonstrated that bone marrow-MSC-derived exosomes containing lncRNA Mir9-3hg improve cardiac function by modulating the RNA-binding protein Pum2 and peroxiredoxin 6, eventually inhibiting cardiomyocyte ferroptosis in mice with I/R injury [73][22].

7. LncRNA HCP5 in Mediating Cardioprotection

LncRNA HLA complex P5 (HCP5), present in the exosomes of human bone marrow MSCs, was identified as a key player in mediating protective effects such as enhanced cardiomyocyte viability and decreased apoptosis during H/R [76][23]. HCP5 is known to interact with miR-497, which targets IGF1 [76,92][23][24]. MSC-derived exosomes containing HCP5 sponged miR-497, leading to activation of the IGF1, PI3K, and AKT pathways and ultimately protected against cardiac I/R injury [76][23].

8. LncRNA UCA1 Protects against Cardiac Injury

Circulating lncRNA urothelial carcinoma-associated 1 (UCA1) may serve as a biomarker for acute myocardial infarction [93,94][25][26]. In addition, UCA1 was associated with electropathology in patients with atrial fibrillation [95][27]. Diao et al. [77][28] studied the role of lncRNA UCA1 present in exosomes derived from human umbilical cord MSCs and found that UCA1 protects against H/R injury in cardiac microvascular endothelial cells using a rat model of I/R injury. The UCA1 in exosomes competitively bound to miR-143, upregulated Bcl-2 expression, and led to the protection of cardiac microvascular endothelial cells against H/R injury [77][28].

9. LncRNA NEAT1 Protects against Cardiac Injuries

Several studies have shown that lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) plays an important role in cardiac diseases [96,97,98][29][30][31]. Exosomes derived from macrophage migration inhibitory factor (MIF)-pretreated MSCs (MIF-exosomes) were shown to protect mouse cardiomyocytes from hydrogen peroxide-mediated cell death [79][32]. This cardioprotective role of MIF-pretreated MSC exosomes was attributed to lncRNA NEAT1 via regulation of miR-142-3p and activating FOXO1 to promote cardiomyocyte survival and to inhibit apoptosis [79][32]. In another study, MIF-pretreated MSC exosomes recovered cardiac function and reduced cellular senescence through the transfer of NEAT1, which inhibits miR-221-3p, activates Sirt2, and counteracts the cardiotoxic effects of doxorubicin [80][33]. The study results demonstrate the cardioprotective roles of lncRNA NEAT1 found in MIF-pretreated MSC exosomes.

10. LncRNA KLF3-AS1 Attenuates Myocardial Infarction

Exosomal lncRNA KLF3-AS1 derived from ischemic cardiomyocytes was shown to play a crucial role in mediating the secretion of IGF-1 by MSCs, thereby rescuing myocardial ischemia/reperfusion injury in both in vivo and in vitro models [99][34]. The lncRNA KLF3-AS1 in exosomes derived from human MSCs was shown to attenuate myocardial infarction by sponging miR-138-5p and activating Sirt1 expression leading to the inhibition of cellular apoptosis and pyroptosis [83][35].

11. LncRNA MALAT1 Prevents Aging-Induced Cardiac Dysfunction

LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been found to be associated with the modulation of myocardial ischemic injury, atherosclerotic progression, cellular senescence, and systemic inflammation [100,101,102][36][37][38]. It shows promise as a potential biomarker for acute myocardial infarction [103][39]. It was found that exosomes derived from human umbilical cord MSCs prevent aging-induced cardiac dysfunction [82][40]. Silencing lncRNA MALAT1 blocked the beneficial effects of these exosomes, suggesting its involvement in inhibiting the NF-κB/TNF-α signaling pathway [82][40]. The study results indicate that MSC-derived exosomes release lncRNA MALAT1, which prevents aging-induced cardiac dysfunction and provides insights into potential therapies for delaying aging and age-related diseases.

12. MSC-Pretreatment-Induced lncRNAs in Mediating Cardioprotection

Various pretreatment methods such as hypoxic preconditioning, treatment with either macrophage migration inhibitory factor (MIF) or atorvastatin, have been shown to facilitate the release of various lncRNAs from exosomes of MSCs and to promote cardiac repair by regulating various microRNAs (miR) and their signaling.
 
Hypoxia preconditioning of human MSCs promoted the generation of exosomes containing lncRNA UCA1 that helped in improving cardiomyocyte survival and cardiac function in a rat model of myocardial infarction (MI) [78][41]. Mechanistically, it was found that UCA1 targeted miR-873 via sponging, leading to XIAP activation, AMPK phosphorylation, and increased expression of the antiapoptotic protein BCL2 [78][41]. In another study, lncRNA MALAT1 present in exosomes derived from hypoxia-preconditioned MSCs acted as a competing endogenous RNA that binds to miR-92a-3p, leading to ATG4a activation and improved mitochondrial metabolism, and ultimately improving doxorubicin-induced cardiomyopathy [81][42]. These findings suggest that exosomes derived from hypoxia-preconditioned MSCs could be a potential therapeutic option for cardiomyopathy.
Exosomes derived from atorvastatin-pretreated MSCs showed enhanced cardioprotective characteristics, promoting endothelial cell function, preventing cardiomyocyte apoptosis, and accelerating migration and tubelike structure formation [84][43]. The involvement of lncRNA H19 as a mediator of these effects was identified, regulating the expression of miR-675, proangiogenic factor VEGF, and intercellular adhesion molecule-1, indicating the enhanced therapeutic potential of atorvastatin-pretreated MSC-derived exosomes in treating acute myocardial infarction by promoting endothelial cell function [84][43].

13. LncRNA XIST Improves Atrial Fibrillation

Elevated levels of lncRNA X-inactive specific transcript (XIST) have been observed in patients with chronic heart failure, indicating its regulatory role in cardiomyocyte function [104][44]. Overexpression of lncRNA XIST in EVs derived from adipose tissue MSCs reduced myocardial pyroptosis and inflammation in atrial fibrillation mouse models and atrial myocytes [75][45]. XIST acted as a competing endogenous RNA (ceRNA) of miR-214-3p, promoting the upregulation of its target gene Arl2, an ADP-ribosylation factor [75][45]. These results suggest that lncRNA XIST can be a potential therapeutic target for atrial fibrillation.

14. LncRNA MIR155HG Improves Vascular Health

Sudden cardiac death risk has been linked to a functional indel polymorphism in the lncRNA MIR155 host gene (MIR155HG) [105][46]. Overexpression of lncRNA MIR155HG in MSCs enhanced their survival, migration, and antiapoptotic properties [70][47]. These protective effects extended to exosomes derived from MIR155HG-overexpressing MSCs, which improved the activity of human umbilical vein endothelial cells, mitigating intimal hyperplasia and ultimately protecting vascular endothelial integrity in a vein graft model using rats [70][47].

15. Inhibition of lncRNA LOC100129516 Promotes Cholesterol Efflux and Alleviates Atherosclerosis

LncRNA LOC100129516 levels were found to be upregulated in macrophage-derived foam cells induced by oxidized low-density lipoproteins [74][48]. In an ApoE-/- atherosclerosis mouse model, exosomal delivery of small interfering RNA against LOC100129516 decreased total cholesterol and low-density lipoprotein levels through activation of the peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα)/phospholipid-transporting ATPase ABCA1 (ABCA1) signaling pathway, promoting cholesterol efflux and suppressing intracellular lipid accumulation [74][48].

16. LncRNA Braveheart Promotes Cardiogenic Differentiation of MSCs In Vitro

lncRNA Braveheart interacts with Mesp1 in regulating the expression of cardiac transcription factors to promote cardiogenic differentiation [106,107][49][50]. Hou et al. [108][51] investigated the role of lncRNA Braveheart in promoting cardiogenic differentiation of MSCs in vitro. They found that transfection of lncRNA Braveheart into MSCs resulted in a higher percentage of differentiated cells with a cardiogenic phenotype compared to control groups through upregulation of cardiac-specific transcription factors (Nkx2.5, Gata4, Gata6, and Isl-1) and epithelial–mesenchymal transition-associated biomarkers (Mesp1, Snail, Twist, and N-cadherin) [108][51]. These findings suggest that lncRNA Braveheart promotes the trans-differentiation of MSCs into cardiogenic cells by enhancing the expression of cardiac-specific transcription factors and epithelial–mesenchymal transition-associated genes including Mesp1. In addition to the above-mentioned MSC-derived lncRNAs, other lncRNAs have been identified as playing a critical role in transcriptional regulation and epigenetic control in cardiac development and cardiovascular diseases. LncRNA CARMN is known to trans-activate the myocardin/serum response factor complex, orchestrating smooth muscle cell differentiation and thwarting atherosclerotic neointima growth [109,110,111][52][53][54]. The lncRNA OIP5-AS1 was implicated in sex-specific differences in mitochondrial function and the development of heart failure, particularly exacerbating heart failure in female mice under cardiac pressure overload conditions [112][55]. LncRNAs like Trdn-as impact mRNA splicing and stability, as exemplified by their interaction with splicing factors to enhance efficient splicing of critical genes like Triadin, essential for calcium handling in cardiomyocytes [113][56]. Additionally, lncRNAs such as ZNF593-AS intercede in splicing processes, affecting excitation–contraction coupling in cardiomyopathy by modulating the splicing of the RYR2 gene [114][57]. The lncRNA myocardial infarction-associated transcript (MIAT) functions as a novel regulator in advanced atherosclerosis, controlling proliferation, apoptosis, and phenotypic transition of smooth muscle cells, along with proinflammatory properties of macrophages [115][58]. The lncRNA cardiac ischemia/reperfusion-associated Ku70 interacting lncRNA (CIRKIL) serves as a detrimental factor in myocardial I/R injury by regulating nuclear translocation of Ku70 and DNA double-strand breaks repair [116][59]. The novel vascular endothelial-associated lncRNA VEAL2 regulates endothelial permeability by competing with diacylglycerol for interaction with protein kinase C beta-b (Prkcbb) and modulating its kinase activity [117][60]. The cytoplasmic lncRNA Caren (short for cardiomyocyte-enriched noncoding transcript) maintains cardiac function by regulating translation of a distant gene, activating mitochondrial bioenergetics, and inactivating the ataxia telangiectasia mutated (ATM)-DNA damage response pathway to ensure cardiomyocyte homeostasis and cardioprotection under pathological stress [118][61].

17. The Role of MSC-Derived circRNA in Cardiac Injury and Repair

circRNAs have emerged as significant regulators in cardiac injury and repair, offering insights into potential therapeutic avenues for myocardial conditions. The cytoplasmic circRNA CircRTN4 was found to alleviate cardiac injury, apoptosis, and oxidative stress in a rat model of sepsis-induced myocardial injury. Further, it was observed that circRTN4 interacted with miR-497-5p to upregulate MG53 expression in cardiomyocytes, thereby mitigating cardiomyocyte damage [51][62]. In another study, circ-0001273 delivered by human umbilical cord MSC-derived exosomes inhibited myocardial cell apoptosis in ischemic conditions, promoting MI repair [52][63]. These studies collectively highlight the therapeutic potential of circRNAs, such as CircRTN4 and circ-0001273, delivered via exosomes, for preventing myocardial injury and promoting cardiac repair. Ruan et al. identified differentially expressed circRNAs that could potentially play roles during the differentiation of human umbilical cord MSCs into cardiomyocyte-like cells [119][64]. The circular RNA circHIPK3 plays a role in regulating cardiomyocyte senescence and cardiac function by acting as a scaffold for p21 mRNA-binding protein HuR and E3 ubiquitin ligase β-TrCP, promoting ubiquitination and degradation of HuR, reducing p21 activity, and influencing cellular senescence and cardiac dysfunction [120][65]. The comprehensive understanding of circRNAs’ regulatory functions in cardiac injury and repair provided by these studies contributes to advancing therapeutic strategies for myocardial conditions.

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