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Expression of Extracellular Vesicle PIWI-Interacting RNAs Throughout hiPSC-Cardiomyocyte Differentiation.

ABSTRACT: Extracellular Vesicles (EV) play a critical role in the regulation of regenerative processes in wounded tissues by mediating cell-to-cell communication. Multiple RNA species have been identified in EV, although their function still lacks understanding. We previously characterized the miRNA content of EV secreted over hiPSC-cardiomyocyte differentiation and found a distinct miRNA expression in hiPSC-EV driving its in vitro bioactivity. In this work, we investigated the piRNA profiles of EV derived from key stages of the hiPSC-CM differentiation and maturation, i.e., from hiPSC (hiPSC-EV), cardiac progenitors (CPC-EV), immature (CMi-EV), and mature (CMm-EV) cardiomyocytes, demonstrating that EV-piRNA expression differs greatly from the miRNA profiles we previously identified. Only four piRNA were significantly deregulated in EV, one in hiPSC-EV, and three in CPC-EV, as determined by differential expression analysis on small RNA-seq data. Our results provide a valuable source of information for further studies aiming at defining the role of piRNA in the bioactivity and therapeutic potential of EV.

SUBMITTER: Louro AF

PROVIDER: S-EPMC9243413 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Extracellular vesicle (EV) miRNome profiling in hiPSC-cardiomyocyte differentiation reveals a stemness-maintenance miRNA cluster driving hiPSC-EV bioactivity

Project description:Extracellular Vesicles (EV) are an attractive therapy to boost cardiac regeneration. Nevertheless, identification of EV and corresponding cell platform(s) suitable for therapeutic application, is still a challenge. Here, we isolated EV from key stages of the human induced pluripotent stem cell-cardiomyocyte (hiPSC-CM) differentiation and maturation, i.e., from hiPSC (hiPSC-EV), cardiac progenitors (CPC-EV), immature (CMi-EV) and mature (CMm-EV) cardiomyocytes, with the aim of identifying a promising cell biofactory for EV production, and pinpoint the genetic signatures of bioactive EV. EV were characterized in terms of expression of specific markers, yield, and size. Bioactivity was assessed in human umbilical vein endothelial cells (HUVEC) and hiPSC-CM. Small RNA-Seq was performed to identify the differentially expressed miRNA in the four EV groups. Bioactivity assays showed increased tube formation and migration in HUVEC treated with hiPSC-EV compared to EV from committed cell populations. hiPSC-EV also significantly increased hiPSC-CM proliferation. Global miRNA expression profiles corroborated an EV-miRNA pattern indicative of stem cell to cardiomyocyte specification. A stemness maintenance miRNA cluster upregulated in hiPSC-EV was found to target the PTEN/PI3K/AKT pathway. Moreover, hiPSC-EV treatment mediated PTEN suppression and increased AKT phosphorylation. Overall, our findings validate hiPSC as suitable cell biofactories for EV production for cardiac regenerative applications.

2022-06-01 | GSE179323 | GEO

PIWI-interacting RNAs are differentially expressed during cardiac differentiation of human pluripotent stem cells.

Project description:PIWI-interacting RNAs (piRNAs) are a class of non-coding RNAs initially thought to be restricted exclusively to germline cells. In recent years, accumulating evidence has demonstrated that piRNAs are actually expressed in pluripotent, neural, cardiac and even cancer cells. However, controversy remains around the existence and function of somatic piRNAs. Using small RNA-seq samples from H9 pluripotent cells differentiated to mesoderm progenitors and cardiomyocytes we identified the expression of 447 piRNA transcripts, of which 241 were detected in pluripotency, 218 in mesoderm and 171 in cardiac cells. The majority of them originated from the sense strand of protein coding and lncRNAs genes in all stages of differentiation, though no evidences of amplification loop (ping-pong) were found. Genes hosting piRNA transcripts in cardiac samples were related to critical biological processes in the heart, like contraction and cardiac muscle development. Our results indicate that these piRNAs might have a role in fine-tuning the expression of genes involved in differentiation of pluripotent cells to cardiomyocytes.

| S-EPMC7199965 | biostudies-literature

PIWI proteins and PIWI-interacting RNAs function in Hydra somatic stem cells.

Project description:PIWI proteins and their bound PIWI-interacting RNAs (piRNAs) are found in animal germlines and are essential for fertility, but their functions outside of the gonad are not well understood. The cnidarian Hydra is a simple metazoan with well-characterized stem/progenitor cells that provides a unique model for analysis of PIWI function. Here we report that Hydra has two PIWI proteins, Hydra PIWI (Hywi) and Hydra PIWI-like (Hyli), both of which are expressed in all Hydra stem/progenitor cells, but not in terminally differentiated cells. We identified ∼15 million piRNAs associated with Hywi and/or Hyli and found that they exhibit the ping-pong signature of piRNA biogenesis. Hydra PIWI proteins are strictly cytoplasmic and thus likely act as posttranscriptional regulators. To explore this function, we generated a Hydra transcriptome for piRNA mapping. piRNAs map to transposons with a 25- to 35-fold enrichment compared with the abundance of transposon transcripts. By sequencing the small RNAs specific to the interstitial, ectodermal, and endodermal lineages, we found that the targeting of transposons appears to be largely restricted to the interstitial lineage. We also identified putative nontransposon targets of the pathway unique to each lineage. Finally we demonstrate that hywi function is essential in the somatic epithelial lineages. This comprehensive analysis of the PIWI-piRNA pathway in the somatic stem/progenitor cells of a nonbilaterian animal suggests that this pathway originated with broader stem cell functionality.

| S-EPMC3890812 | biostudies-literature

Expression and Regulation of PIWIL-Proteins and PIWI-Interacting RNAs in Rheumatoid Arthritis.

Project description:ObjectiveThe PIWIL (P-element induced wimpy testis like protein) subfamily of argonaute proteins is essential for Piwi-interacting RNA (piRNA) biogenesis and their function to silence transposons during germ-line development. Here we explored their presence and regulation in rheumatoid arthritis (RA).MethodsThe expression of PIWIL genes in RA and osteoarthritis (OA) synovial tissues and synovial fibroblasts (SF) was analysed by Real-time PCR, immunofluorescence and Western blot. The expression of piRNAs was quantified by next generation small RNA sequencing (NGS). The regulation of PIWI/piRNAs, proliferation and methylation of LINE-1 after silencing of PIWIL genes were studied.ResultsPIWIL2 and 4 mRNA were similarly expressed in synovial tissues and SF from RA and OA patients. However, on the protein level only PIWIL4 was strongly expressed in SF. Using NGS up to 300 piRNAs were identified in all SF without significant differences in expression levels between RA and OASF. Of interest, the analysis of the co-expression of the detected piRNAs revealed a less tightly regulated pattern of piRNA-823, -4153 and -16659 expression in RASF. In RASF and OASF, stimulation with TNF?+IL1?/TLR-ligands further significantly increased the expression levels of PIWIL2 and 4 mRNA and piRNA-16659 was significantly (4-fold) induced upon Poly(I:C) stimulation. Silencing of PIWIL2/4 neither affect LINE-1 methylation/expression nor proliferation of RASF.ConclusionWe detected a new class of small regulatory RNAs (piRNAs) and their specific binding partners (PIWIL2/4) in synovial fibroblasts. The differential regulation of co-expression of piRNAs in RASF and the induction of piRNA/Piwi-proteins by innate immune stimulators suggest a role in inflammatory processes.

| S-EPMC5125648 | biostudies-literature

Piwi-interacting RNAs and PIWI genes as novel prognostic markers for breast cancer.

Project description:Piwi-interacting RNAs (piRNAs), whose role in germline maintenance has been established, are now also being classified as post-transcriptional regulators of gene expression in somatic cells. PIWI proteins, central to piRNA biogenesis, have been identified as genetic and epigenetic regulators of gene expression. piRNAs/PIWIs have emerged as potential biomarkers for cancer but their relevance to breast cancer has not been comprehensively studied. piRNAs and mRNAs were profiled from normal and breast tumor tissues using next generation sequencing and Agilent platforms, respectively. Gene targets for differentially expressed piRNAs were identified from mRNA expression dataset. piRNAs and PIWI genes were independently assessed for their prognostic significance (outcomes: Overall Survival, OS and Recurrence Free Survival, RFS). We discovered eight piRNAs as novel independent prognostic markers and their association with OS was confirmed in an external dataset (The Cancer Genome Atlas). Further, PIWIL3 and PIWIL4 genes showed prognostic relevance. 306 gene targets exhibited reciprocal relationship with piRNA expression. Cancer cell pathways such as apoptosis and cell signaling were the key Gene Ontology terms associated with the regulated gene targets. Overall, we have captured the entire cascade of events in a dysregulated piRNA pathway and have identified novel markers for breast cancer prognostication.

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Project description:PIWI-interacting RNAs (piRNAs) are at the center of a small RNA-based immune system that defends genomes against the deleterious action of mobile genetic elements (transposons). PiRNAs are highly variable in sequence with extensive targeting potential. Their diversity is restricted by their preference to start with a Uridine (U) at the 5' most position (1U-bias), a bias that remains poorly understood. Here we uncover that the 1U-bias of Piwi-piRNAs is established by consecutive discrimination against all nucleotides but U, first during piRNA biogenesis and then upon interaction with Piwi's specificity loop. Sequence preferences during piRNA processing also restrict U across the piRNA body with the potential to directly impact target recognition. Overall, the uncovered signatures could modulate specificity and efficacy of piRNA-mediated transposon restriction, and provide a substrate for purifying selection in the ongoing arms race between genomes and their mobile parasites.

| S-EPMC6381166 | biostudies-literature

PIWI-interacting RNAs and PIWI proteins in glioma: molecular pathogenesis and role as biomarkers.

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| S-EPMC7590611 | biostudies-literature

Global Analyses of Expressed Piwi-Interacting RNAs in Gastric Cancer.

Project description:Gastric cancer (GC) represents a notable amount of morbidity and mortality worldwide. Understanding the molecular basis of CG will offer insight into its pathogenesis in an attempt to identify new molecular biomarkers to early diagnose this disease. Therefore, studies involving small non-coding RNAs have been widely explored. Among these, PIWI-interacting RNAs (piRNAs) are an emergent class that can play important roles in carcinogenesis. In this study, small-RNA sequencing was used to identify the global piRNAs expression profile (piRNome) of gastric cancer patients. We found 698 piRNAs in gastric tissues, 14 of which were differentially expressed (DE) between gastric cancer (GC), adjacent to gastric cancer (ADJ), and non-cancer tissues (NC). Moreover, three of these DE piRNAs (piR-48966*, piR-49145, piR-31335*) were differently expressed in both GC and ADJ samples in comparison to NC samples, indicating that the tumor-adjacent tissue was molecularly altered and should not be considered as a normal control. These three piRNAs are potential risk biomarkers for GC, especially piR-48966* and piR-31335*. Furthermore, an in-silico search for mRNAs targeted by the differentially expressed piRNAs revealed that these piRNAs may regulate genes that participate in cancer-related pathways, suggesting that these small non-coding RNAs may be directly and indirectly involved in gastric carcinogenesis.

| S-EPMC7593925 | biostudies-literature

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Project description:PIWI-interacting RNAs (piRNAs) are emerging players in cancer genomics. Originally described in the germline, there are over 20,000 piRNA genes in the human genome. In contrast to microRNAs, piRNAs interact with PIWI proteins, another member of the Argonaute family, and function primarily in the nucleus. There, they are involved in the epigenetic silencing of transposable elements in addition to the transcriptional regulation of genes. It has recently been demonstrated that piRNAs are also expressed across a variety of human somatic tissue types in a tissue-specific manner. An increasing number of studies have shown that aberrant piRNA expression is a signature feature across multiple tumour types; however, their specific tumorigenic functions remain unclear. In this article, we discuss the emerging functional roles of piRNAs in a variety of cancers, and highlight their potential clinical utilities.

| S-EPMC4714483 | biostudies-literature

PIWI-interacting RNAs: Mitochondria-based biogenesis and functions in cancer.

Project description:PIWI-interacting RNA (piRNAs), once thought to be mainly functioning in germlines, are now known to play an essential role in somatic and cancerous tissues. Ping-pong cycle initiation and mitochondria-based phased production constitute the core of the piRNA biogenesis and these two processes are well conserved in mammals, including humans. By being involved in DNA methylation, histone marker deposition, mRNA degradation, and protein modification, piRNAs also contribute to carcinogenesis partly due to oncogenic stress-induced piRNA dysregulation. Also, piRNAs play important roles in cancer stemness, drug resistance, and tumor immunology. Results from liquid biopsy analysis of piRNA can be used in both cancer diagnoses and cancer prognoses. A combination of targeting piRNA with other therapeutic strategies could be groundbreaking cancer treatment.

| S-EPMC8278532 | biostudies-literature

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