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Transient let-7/miR-98 reprograms primed pluripotency to induce naive human PSCs

ABSTRACT: Naive human pluripotent stem cells (hPSCs) are valuable for modeling early development and enabling regenerative applications, yet resetting from the primed state remains inefficient and mechanistically unclear. We identify an unexpected role for miR-98-5p, a let-7 family microRNA (miRNA) typically linked to differentiation, in promoting naive induction. Using a synthetic mRNA screen containing diverse miRNA-responsive elements, we uncovered miR-98-5p as a potent enhancer of resetting. Single-cell RNA sequencing and targeted perturbations show that miR-98-5p directly represses NR6A1 while transiently activating BMP2/4 signaling, triggering network transitions. These changes destabilize the primed gene-regulatory network and enable acquisition of a naive state. Leveraging this mechanism, we establish a feeder-free, miRNA-based, editing-free protocol that boosts resetting efficiency from <10% to ~80%. To our knowledge, this is the first demonstration that a let-7 miRNA can drive naive induction by coupling direct target repression with activation of pro-naive signaling, suggesting a generalizable reprogramming principle of transient network destabilization.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE280065 | GEO | 2026/08/31

REPOSITORIES: GEO

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Project description:Abstract Objectives: Abdominal aortic aneurysm (AAA) is a fatal cardiovascular disease with no effective drug treatment currently available. The aberrant expressions of microRNAs (miRNAs) contribute to AAA pathogenesis. In this study, we aimed to perform miRNA microarray analysis to screen for differentially expressed miRNAs in the aortas of AAA mice compared to those in control mice, and to clarify the role and mechanism of miRNA-378a-5p (miR-378a-5p) in the AAA development. Methods: We performed a comprehensive miRNA microarray analysis to screen for differentially expressed miRNAs in the aortas of AAA mice and control mice. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expressions of miR-378a-5p in the serum and aortas of AAA patients and mice. To clarify the role of miR-378a-5p in the AAA development in vivo, miR-378a-5p antagomir and angomir were administered to ApoE-/- mice using tail venous injection, followed by Angiotensin II (Ang II) infusion. Next, the role of miR-378a-5p in the phenotypic switching and migration of vascular smooth muscle cells (VSMCs) was examined in vivo and in vitro. Mechanistically, the targets of miR-378a-5p were identified by bioinformatics analysis, luciferase assay, qRT-PCR and western blot. Co-immunoprecipitation (Co-IP) assay combined with mass spectrometry were carried out for excavating potential downstream effectors. Results: The expression of miR-378a-5p was decreased in the serum and aortas of AAA patients and mice, and tumor necrosis factor-α (TNFα)-treated VSMCs. In vivo, the antagomir-378a-5p aggravated AAA formation, as evidenced by a larger maximal aortic diameter and greater medial elastin degradation than in control mice. MiR-378a-5p angomir had the opposite effect. In vitro, miR-378a-5p overexpression significantly promoted the contraction ability and suppressed the migration of VSMCs, whereas miR-378a-5p knockdown inhibited the contraction ability and increased the migration of VSMCs. Mechanistically, we discovered that miR-378a-5p played a protective role in AAA development by regulating actin-binding LIM protein 1 (ABLIM1)-megakaryoblastic leukemia 1 (MKL1) pathway. Conclusion: MiR-378a-5p exerts protective effects against AAA by maintaining VSMCs homeostasis via the ABLIM1-MKL1 pathway. Therefore, targeting miR-378a-5p may be an attractive therapeutic strategy for AAA treatment.

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Transient let-7/miR-98 reprograms primed pluripotency to induce naive human PSCs

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