Intratesticular Peptidyl Prolyl Isomerase 1 Protein Delivery Using Cationic Lipid-Coated Fibroin Nanoparticle Complexes Rescues Male Infertility in Mice

Kim, Woo Jin; Kim, Bong Soo; Kim, Hyun Jung; Cho, Young‐Dan; Shin, Hye Lim; Yoon, Hee In; Lee, Yun Sil; Baek, Jeong‐Hwa; Woo, Kyung Mi; Ryoo, Hyun‐Mo

doi:10.1021/acsnano.0c04936

Cited by 13 publications

(9 citation statements)

References 83 publications

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“…For example, Kim et al developed a nanoparticle complex with PIN1 proteins inside to treat infertile mice that were lacking the PIN1 protein. These experiments successfully restore the fertility of the mice [ 70 ]. It has recently been suggested that proteins offer advantages over other small molecules regarding their use as therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Landscape of Human Sperm in Patients with Different Spermatogenic Impairments

Becker

Smadi

Räschle

et al. 2023

Cells

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Although the proteome of sperm has been characterized, there is still a lack of high-throughput studies on dysregulated proteins in sperm from subfertile men, with only a few studies on the sperm proteome in asthenozoospermic and oligoasthenozoospermic men. Using liquid chromatography–mass spectrometry (LC-MS/MS) along with bioinformatics analyses, we investigated the proteomic landscape of sperm collected from subfertile men (n = 22), i.e., asthenozoospermic men (n = 13), oligoasthenozoospermic men (n = 9) and normozoospermic controls (n = 31). We identified 4412 proteins in human sperm. Out of these, 1336 differentially abundant proteins were identified in 70% of the samples. In subfertile men, 32 proteins showed a lower abundance level and 34 showed a higher abundance level when compared with normozoospermic men. Compared to normozoospermic controls, 95 and 8 proteins showed a lower abundance level, and 86 and 1 proteins showed a higher abundance level in asthenozoospermic and oligoasthenozoospermic men, respectively. Sperm motility and count were negatively correlated with 13 and 35 and positively correlated with 37 and 20 differentially abundant proteins in asthenozoospermic and oligoasthenozoospermic men, respectively. The combination of the proteins APCS, APOE, and FLOT1 discriminates subfertile males from normozoospermic controls with an AUC value of 0.95. Combined APOE and FN1 proteins discriminate asthenozoospermic men form controls with an AUC of 1, and combined RUVBL1 and TFKC oligoasthenozoospermic men with an AUC of 0.93. Using a proteomic approach, we revealed the proteomic landscape of sperm collected from asthenozoospermic or oligoasthenozoospermic men. Identified abundance changes of several specific proteins are likely to impact sperm function leading to subfertility. The data also provide evidence for the usefulness of specific proteins or protein combinations to support future diagnosis of male subfertility.

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Section: Discussionmentioning

confidence: 99%

Proteomic Landscape of Human Sperm in Patients with Different Spermatogenic Impairments

Becker

Smadi

Räschle

et al. 2023

Cells

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“…PIN1 has also been pinpointed as a seminal biomarker for higher fertility in porcine models [ 43 ]. Finally, we wish to highlight a recent study where the intracellular injection of PIN1 lipid nanoparticles in knockout mice ( Pin1 −/− ) resulted in the regulation of spermatogonial proliferation and differentiation and in the restructuring of the BTB, thus rescuing fertility in male mice [ 44 ]. Therefore, we consider that our findings encourage the analysis of PIN1 as a therapeutic target to restore human male fertility.…”

Section: Discussionmentioning

confidence: 99%

Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

Cerván-Martín¹,

Bossini‐Castillo²,

Guzmán-Jiménez³

et al. 2022

JPM

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We aimed to analyze the role of the common genetic variants located in the PIN1 locus, a relevant prolyl isomerase required to control the proliferation of spermatogonial stem cells and the integrity of the blood–testis barrier, in the genetic risk of developing male infertility due to a severe spermatogenic failure (SPGF). Genotyping was performed using TaqMan genotyping assays for three PIN1 taggers (rs2287839, rs2233678 and rs62105751). The study cohort included 715 males diagnosed with SPGF and classified as suffering from non-obstructive azoospermia (NOA, n = 505) or severe oligospermia (SO, n = 210), and 1058 controls from the Iberian Peninsula. The allelic frequency differences between cases and controls were analyzed by the means of logistic regression models. A subtype specific genetic association with the subset of NOA patients classified as suffering from the Sertoli cell-only (SCO) syndrome was observed with the minor alleles showing strong risk effects for this subset (ORaddrs2287839 = 1.85 (1.17–2.93), ORaddrs2233678 = 1.62 (1.11–2.36), ORaddrs62105751 = 1.43 (1.06–1.93)). The causal variants were predicted to affect the binding of key transcription factors and to produce an altered PIN1 gene expression and isoform balance. In conclusion, common non-coding single-nucleotide polymorphisms located in PIN1 increase the genetic risk to develop SCO.

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“…The genetic deletion of PIN1 may lead to testicular atrophy and a consequent reduction in fertility ( 31 ). Recent studies showed that PIN1 participates in the maintenance of BTB function and integrity by regulating the expression of junction proteins between SCs: connexin43 (Cx43; gap junction) and N-cadherin (CDH2; adhesion junction), and its deficiency results in the destruction of BTB integrity ( 32 , 33 ). In the present study, PIN1 was identified as having a significantly increased abundance in postpubertal testes, a finding suggestive of an active role for the PIN1 gene in BTB function during sheep spermatogenesis.…”

Section: Discussionmentioning

confidence: 99%

Integrating miRNA and mRNA Profiling to Assess the Potential miRNA–mRNA Modules Linked With Testicular Immune Homeostasis in Sheep

Wang

Luo

et al. 2021

Front. Vet. Sci.

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Beyond its well-known role in spermatogenesis and androgen production, mammalian testes are increasingly recognized as an immune-privileged organ for protecting autoantigenic germ cells, especially meiotic and postmeiotic germ cells, from systemic immune responses. Despite its importance, the molecular mechanisms underlying this regulation in mammals, including sheep, are far from known. In this study, we searched for the genes associated with testicular immune privilege and assessed their possible modulating mechanisms by analyzing systematic profiling of mRNAs and miRNAs on testicular tissues derived from prepubertal and postpubertal Tibetan sheep acquired by RNA sequencing. We identified 1,118 differentially expressed (DE) mRNAs associated with immunity (245 increased mRNAs and 873 decreased mRNAs) and 715 DE miRNAs (561 increased miRNAs and 154 decreased miRNAs) in postpubertal testes compared with prepuberty. qPCR validations for 20 DE mRNAs and 16 miRNAs showed that the RNA-seq results are reliable. By using Western blot, the postpubertal testes exhibited decreased protein abundance of CD19 and TGFBR2 (two proteins encoded by DE mRNAs) when compared with prepuberty, consistent with mRNA levels. The subsequent immunofluorescent staining showed that the positive signals for the CD19 protein were observed mainly in Sertoli cells and the basement membrane of pre- and postpubertal testes, as well as the prepubertal testicular vascular endothelium. The TGFBR2 protein was found mostly in interstitial cells and germ cells of pre- and postpubertal testes. Functional enrichment analysis indicated that DE mRNAs were mainly enriched in biological processes or pathways strongly associated with the blood–testis barrier (BTB) function. Many decreased mRNAs with low expression abundance were significantly enriched in pathways related to immune response. Also, multiple key miRNA-target negative correlation regulatory networks were subsequently established. Furthermore, we verified the target associations between either oar-miR-29b or oar-miR-1185-3p and ITGB1 by dual-luciferase reporter assay. Finally, a putative schematic model of the miRNA-mRNA-pathway network mediated by immune homeostasis-related genes was proposed to show their potential regulatory roles in sheep testicular privilege. Taken together, we conclude that many immune-related genes identified in this study are negatively regulated by potential miRNAs to participate in the homeostatic regulation of testicular immune privilege of sheep by sustaining BTB function and inhibiting immune responses under normal physiological conditions. This work offers the first global view of the expression profiles of miRNAs/mRNAs involved in sheep testicular immune privilege and how the genes potentially contribute to immune-homeostatic maintenance.

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Intratesticular Peptidyl Prolyl Isomerase 1 Protein Delivery Using Cationic Lipid-Coated Fibroin Nanoparticle Complexes Rescues Male Infertility in Mice

Cited by 13 publications

References 83 publications

Proteomic Landscape of Human Sperm in Patients with Different Spermatogenic Impairments

Proteomic Landscape of Human Sperm in Patients with Different Spermatogenic Impairments

Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

Integrating miRNA and mRNA Profiling to Assess the Potential miRNA–mRNA Modules Linked With Testicular Immune Homeostasis in Sheep

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