Plurisomes™ : news

Cross-species comparison reveals that Hmga1 reduces H3K27me3 levels to promote cardiomyocyte proliferation and cardiac regeneration.

admin — Thu, 02 Jan 2025 00:00:00 +0000

In contrast to adult mammalian hearts, the adult zebrafish heart efficiently replaces cardiomyocytes lost after injury. Here we reveal shared and species-specific injury response pathways and a correlation between Hmga1, an architectural non-histone protein, and regenerative capacity, as Hmga1 is required and sufficient to induce cardiomyocyte proliferation and required for heart regeneration. In addition, Hmga1 was shown to reactivate developmentally silenced genes, likely through modulation of H3K27me3 levels, poising them for a pro-regenerative gene program. Furthermore, AAV-mediated Hmga1 expression in injured adult mouse hearts led to controlled cardiomyocyte proliferation in the border zone and enhanced heart function, without cardiomegaly and adverse remodeling. Histone modification mapping in mouse border zone cardiomyocytes revealed a similar modulation of H3K27me3 marks, consistent with findings in zebrafish. Our study demonstrates that Hmga1 mediates chromatin remodeling and drives a regenerative program, positioning it as a promising therapeutic target to enhance cardiac regeneration after injury.

https://pubmed.ncbi.nlm.nih.gov/39747457/

Exosomal miR-17-5p from human embryonic stem cells prevents pulmonary fibrosis by targeting thrombospondin-2.

admin — Mon, 04 Sep 2023 00:00:00 +0000

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease characterized by pulmonary fibrosis and lung dysfunction, ultimately leading to respiratory failure. Many preclinical studies have investigated the therapeutic potential of stem cell-derived exosomes in this disease, particularly mesenchymal stem cell-derived exosomes. However, the effects of embryonic stem cell-derived exosomes in IPF remain unclear.

We established a bleomycin (BLM)-induced pulmonary fibrosis mice model and administered human embryonic stem cell exosomes (hESC-exo) from the first day after BLM treatment. The effects of hESC-exo were assessed by pulmonary function tests, biochemical analysis, histochemistry, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). RNA-seq was used to screen for the potential therapeutic targets of hESC-exo in fibrotic lungs; the identified signaling axis was characterized using a luciferase assay, qPCR, and WB.

Results indicated hESC-exo administration notably alleviated inflammation, removed deposited collagen, and rescued alveolar architecture in the lungs of BLM-induced mice. In vivo and in vitro tests revealed that hESC-exo-derived miR-17-5p directly bound thrombospondin-2 (Thbs2) to regulate inflammation and fibrosis; thus, hESC-exo protected against BLM toxicity in the lungs via the miR-17-5p/Thbs2 axis.

These results suggest a promising new treatment for fibrosis-associated diseases.

https://pubmed.ncbi.nlm.nih.gov/37667335/

An African-specific variant of TP53 reveals PADI4 as a regulator of p53-mediated tumor suppression.

admin — Thu, 04 May 2023 00:00:00 +0000

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific, germline variant of TP53 in the DNA binding domain, Tyr107His (Y107H). NMR and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the non-natural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases, and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive, and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune checkpoint inhibitors.

https://pubmed.ncbi.nlm.nih.gov/37140445/

MicroRNAs in POI, DOR and POR.

admin — Sat, 25 Feb 2023 00:00:00 +0000

Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years. However, the etiology of approximately 90% patients remains unknown. Diminished ovarian reserve (DOR) and poor ovarian response (POR) are related to POI in clinic. The main purpose of this review was to evaluate the roles of microRNAs (miRNAs) in the pathogenesis and therapeutic potential for POI, DOR and POR.

A literature search was conducted using six databases (PubMed, EMBASE, Web of Science, Cochrane Library, CNKI and Wangfang Data) to obtain relevant studies.

This review enlightens expression profiles and functional studies of miRNAs in ovarian insufficiency in animal models and humans. Functional studies emphasized the role of miRNAs in steroidogenesis, granulosa cell proliferation/apoptosis, autophagy and follicular development by regulating target genes in specific pathways, such as the PI3K/AKT/mTOR, TGFβ, MAPK and Hippo pathways. Differentially expressed circulating miRNAs provided novel biomarkers for diagnosis and prediction, such as miR-22-3p and miR-21. Moreover, exosomes derived from stem cells restored ovarian function through miRNAs in chemotherapy-induced POI models.

Differential miRNA expression profiles in patients and animal models uncovered the underlying mechanisms and biomarkers of ovarian insufficiency. Exosomal miRNAs can restore ovarian function against chemotherapy-induced POI, which needs further investigation to develop novel preventive and therapeutic strategies in clinical practice.

https://pubmed.ncbi.nlm.nih.gov/36840768/

Low expression of ZSCAN4 predicts unfavorable outcome in urothelial carcinoma of upper urinary tract and urinary bladder.

admin — Sat, 25 Feb 2023 00:00:00 +0000

With the advance in genome-wide analyses, genetic alternations have been found to play an important role in carcinogenesis and aggressiveness of UC. Through bioinformatic analysis of gene expression profiles of urinary bladder urothelial carcinoma (UBUC) from publicly available GEO dataset (GSE31684), Zinc finger and SCAN domain containing 4 (ZSCAN4) was identified as a significant downregulated gene in muscle-invasive bladder cancer when compared with non-muscle-invasive bladder cancer.

The expression of ZSCAN4 was evaluated by immunohistochemistry in 340 upper urinary tract urothelial carcinomas (UTUCs) and 295 UBUCs. The expression profiles of ZSCAN4 and potential signaling pathways were analyzed bioinformatically.

In UTUC, low expression of ZSCAN4 was significantly associated with advanced primary pT stage (P = 0.011), increased nodal metastasis (P = 0.002) and increased vascular invasion (P = 0.019). In UBUC, low expression of ZSCAN4 was significantly correlated with advanced primary pT stage (P < 0.001), increased nodal metastasis (P = 0.001), high histological grade (P = 0.003) and increased vascular invasion (P = 0.003). In survival analysis, low expression of ZSCAN4 acted as an independent negative prognostic factor for disease-specific survival and metastasis-free survival both in UTUC and UBUC. Gene ontology analysis showed that ZSCAN4 mRNA and its co-downregulated genes are associated with the mitotic cell cycle.

Low expression of ZSCAN4 predicted worse outcome in urothelial carcinoma and might have potential regulatory role in cell mitosis.

https://pubmed.ncbi.nlm.nih.gov/36841776/

Regenerative medicine strategies for hair growth and regeneration: A narrative review of literature.

admin — Mon, 31 Oct 2022 00:00:00 +0000

Hair loss, or alopecia, is associated with several psychosocial and medical comorbidities, and it remains an economic burden to individuals and the society. Alopecia is attributable to varied mechanisms and features a multifactorial predisposition, and the available conventional medical interventions have several limitations. Thus, several therapeutic strategies for alopecia in regenerative medicine are currently being explored, with increasing evidence suggesting that mesenchymal stem cell (MSC) implantation, MSC-derived secretome treatment, and blood-derived platelet-rich plasma therapies are potential treatment options. In this review, we searched the Cochrane Library, MEDLINE (PubMed), EMBASE, and Scopus using various combinations of terms, such as "stem cell," "alopecia," "hair loss," "Androgenetic alopecia," "male-pattern hair loss," "female-pattern hair loss," "regenerative hair growth," "cell therapy," "mesenchymal stem cells," "MSC-derived extracellular vesicles," "MSC-derived exosomes," and "platelet-rich plasma" and summarized the most promising regenerative treatments for alopecia. Moreover, further opportunities of improving efficacy and innovative strategies for promoting clinical application were discussed.

Paracrine factor	Activity on hair growth
VEGF	Improves perifollicular angiogenesis, resulting in increased size of HFs and shafts.
HGF	Activators enhance the proliferation of follicular epithelial cells
EGF	Improves the activity and growth of follicle outer-root sheath cells by activating Wnt/β-catenin flagging
PDGF and receptor	Induces and maintains anagen phase of hair cycle.
IL-6	Is involved in wound-induced hair neogenesis through STAT3 activation
IGF-I	Improves the migration, survival, and proliferation of HF cells
IGFBP1–6	Manage the effect of IGF-1 and its connection with ECM proteins at the HF level
TGF-β	Stimulates the signaling pathways that manage the hair cycle
KGF (FGF-10)	Stimulates proliferation and differentiation of early progenitor cells within HFs. Induces anagen phase in resting HFs.
FGF-1, FGF-2	Induces anagen phase in resting HFs.
bFGF	Improves the advancement of HFs
BMP	Maintains the DPC phenotype
BMPR1a	Maintains the proper identity of DPCs
M-CSF and receptor	Is involved in wound-induced hair growth
Wnt3a	Is involved in HF advancement through β-catenin flagging
PGE2	Stimulates anagen in HFs
PGF2α and analogs	Enhance the change from telogen to anagen.

https://pubmed.ncbi.nlm.nih.gov/36382136/

lncRNA-H19 in Fibroblasts Promotes Wound Healing in Diabetes.

admin — Fri, 01 Jul 2022 00:00:00 +0000

Cutaneous wound healing in diabetes is impaired and would develop into nonhealing ulcerations. However, the molecular mechanism underlying the wound-healing process remains largely obscure. Here, we found that cutaneous PDGFRα+ fibroblast-expressing lncRNA-H19 (lncH19) accelerates the wound-healing process via promoting dermal fibroblast proliferation and macrophage infiltration in injured skin. PDGFRα+ cell-derived lncH19, which is lower in contents in the wound-healing cutaneous tissue of patients and mice with type 2 diabetes, is required for wound healing through promoting proliferative capacity of dermis fibroblasts as well as macrophage recruitments. Mechanistically, lncH19 relieves the cell cycle arrest of fibroblasts and increases macrophage infiltration in injured tissues via inhibiting p53 activity and GDF15 releasement. Furthermore, exosomes derived from adipocyte progenitor cells efficiently restore the impaired diabetic wound healing via delivering lncH19 to injured tissue. Therefore, our study reveals a new role for lncRNA in regulating cutaneous tissue repair and provides a novel promising insight for developing clinical treatment of diabetes.

https://pubmed.ncbi.nlm.nih.gov/35472819/

Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state.

admin — Thu, 30 Jun 2022 00:00:00 +0000

Hair follicle stem cells are regulated by dermal papilla fibroblasts, their principal signaling niche. Overactivation of Hedgehog signaling in the niche dramatically accelerates hair growth and induces follicle multiplication in mice. On single-cell RNA sequencing, dermal papilla fibroblasts increase heterogeneity to include new Wnt5a states. Transcriptionally, mutant fibroblasts activate regulatory networks for Gli1, Alx3, Ebf1, Hoxc8, Sox18, and Zfp239. These networks jointly upregulate secreted factors for multiple hair morphogenesis and hair-growth-related pathways. Among these is non-conventional TGF-β ligand Scube3. We show that in normal mouse skin, Scube3 is expressed only in dermal papillae of growing, but not in resting follicles. SCUBE3 protein microinjection is sufficient to induce new hair growth, and pharmacological TGF-β inhibition rescues mutant hair hyper-activation phenotype. Moreover, dermal-papilla-enriched expression of SCUBE3 and its growth-activating effect are partially conserved in human scalp hair follicles. Thus, Hedgehog regulates mesenchymal niche function in the hair follicle via SCUBE3/TGF-β mechanism.

https://pubmed.ncbi.nlm.nih.gov/35777353/

MSCs-Derived miR-150-5p-Expressing Exosomes Promote Skin Wound Healing by Activating PI3K/AKT Pathway through PTEN.

admin — Thu, 30 Jun 2022 00:00:00 +0000

The goal of this study was to investigate the mechanism of mesenchymal stem cell (MSC)-derived microRNA (miR)-150-5p-expressing exosomes in promoting skin wound healing through activating PI3K/AKT pathway by PTEN.

Human umbilical cord (HUC)-MSCs were infected with miR-150-5p overexpression and its control lentivirus, and HUC-MSCs-derived exosomes (MSCs-Exos) with stable expression of miR-150-5p were obtained. HaCaT cells were induced by HHO to establish a cellular model of skin injury, in which the expression of miR-150-5p and PTEN and the phosphorylation of PI3K and AKT were evaluated. HaCaT cells were transfected with pcDNA3.1-PTEN or pcDNA3.1 and then cultured with normal exosomes or exosomes stably expressing miR-150-5p. Cell proliferation was inspected by CCK-8. Cell migration was detected by scratch test and cell apoptosis by flow cytometry. The starBase tool was used to predict the binding site of miR-150-5p to PTEN. Dual-luciferase reporter assay and RIP assay were applied to assess the interaction between miR-150-5p and PTEN. In HHO-induced HaCaT cells, the miR-150-5p expression decreased, and PTEN expression increased in a concentration-dependent manner. MSCs-Exos promoted the growth and migration of HHO-induced HaCaT cells and inhibited their apoptosis. In addition, overexpression of exosomal miR-150-5p enhanced the protective effect of MSCs-Exos on HHO-induced HaCaT cells; PTEN overexpression in HaCaT cells partially restrained miR-150-5p-mediated inhibition on HHO-induced injury in HaCaT cells. PTEN was a target gene of miR-150-5p. MiR-150-5p regulated PI3K/AKT pathway through PTEN.

MSCs-derived miR-150-5p-expressing exosomes promote skin wound healing by activating PI3K/AKT pathway through PTEN.

https://pubmed.ncbi.nlm.nih.gov/35769052/