Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

Melnik, Bodo C.; Schmitz, Gerd

doi:10.3390/ijms231911503

Cited by 9 publications

(4 citation statements)

References 570 publications

(899 reference statements)

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“…Weaning, the termination of breastmilk, maternal antibodies, and MDE miRs, may initiate an “epigenetic switch” attenuating BCL6 and enhancing BLIMP1 expression required for B cell differentiation to plasma cells and own antibody secretion by the infant [ 557 ]. This scenario is in accordance with the MDE miR-mediated switch of proliferating pancreatic β-cells to differentiated insulin-secreting matured β-cells after weaning [ 562 , 563 ]. Continued consumption of commercial cow’s milk via transfer of highly conserved MDE miRs may not only de-differentiate the pancreatic β-cell back to the neonatal phenotype but may also over-stimulate BCL6-driven B cell proliferation, a potential driving force in the pathogenesis of DLBCL ( Figure 4 ).…”

Section: Discussionsupporting

confidence: 72%

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

Melnik

Stadler

Weiskirchen

et al. 2023

IJMS

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Epidemiological evidence supports an association between cow’s milk consumption and the risk of diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma worldwide. This narrative review intends to elucidate the potential impact of milk-related agents, predominantly milk-derived exosomes (MDEs) and their microRNAs (miRs) in lymphomagenesis. Upregulation of PI3K-AKT-mTORC1 signaling is a common feature of DLBCL. Increased expression of B cell lymphoma 6 (BCL6) and suppression of B lymphocyte-induced maturation protein 1 (BLIMP1)/PR domain-containing protein 1 (PRDM1) are crucial pathological deviations in DLBCL. Translational evidence indicates that during the breastfeeding period, human MDE miRs support B cell proliferation via epigenetic upregulation of BCL6 (via miR-148a-3p-mediated suppression of DNA methyltransferase 1 (DNMT1) and miR-155-5p/miR-29b-5p-mediated suppression of activation-induced cytidine deaminase (AICDA) and suppression of BLIMP1 (via MDE let-7-5p/miR-125b-5p-targeting of PRDM1). After weaning with the physiological termination of MDE miR signaling, the infant’s BCL6 expression and B cell proliferation declines, whereas BLIMP1-mediated B cell maturation for adequate own antibody production rises. Because human and bovine MDE miRs share identical nucleotide sequences, the consumption of pasteurized cow’s milk in adults with the continued transfer of bioactive bovine MDE miRs may de-differentiate B cells back to the neonatal “proliferation-dominated” B cell phenotype maintaining an increased BLC6/BLIMP1 ratio. Persistent milk-induced epigenetic dysregulation of BCL6 and BLIMP1 expression may thus represent a novel driving mechanism in B cell lymphomagenesis. Bovine MDEs and their miR cargo have to be considered potential pathogens that should be removed from the human food chain.

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Section: Discussionsupporting

confidence: 72%

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

Melnik

Stadler

Weiskirchen

et al. 2023

IJMS

Self Cite

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“…Milk was the only commercially available bio-liquid containing EXO. As a rich source of EXO, milk has unique properties as a carrier [ 26 ] which had been utilized in enhancing the anticancer activity against oral squamous cell carcinoma [ 27 ] and treating the ovarian cancer [ 28 ]. On the basis of our group’s previous studies, it has been reported that bovine milk-derived exosomes as a drug delivery vehicle has played an important role in miRNA-based therapy to accelerate the diabetic wound healing.…”

Section: Discussionmentioning

confidence: 99%

Milk-derived exosomes carrying siRNA-KEAP1 promote diabetic wound healing by improving oxidative stress

Xiang

Chen

Jiang

et al. 2023

Drug Deliv. and Transl. Res.

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Diabetic wounds are a serious complication of diabetes mellitus (DM) that can lead to persistent infection, amputation, and even death. Prolonged oxidative stress has been widely recognized as a major instigator in the development of diabetic wounds; therefore, oxidative stress is considered a promising therapeutic target. In the present study, Keap1/Nrf2 signaling was confirmed to be activated in streptozotocin (STZ)-induced diabetic mice and methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). Knockdown of Keap1 by siRNA reversed the increase in Keap1 levels, promoted the nuclear translocation of Nrf2, and increased the expression of HO-1, an antioxidant protein. To explore therapeutic delivery strategies, milk-derived exosomes (mEXOs) were developed as a novel, efficient, and non-toxic siRNA carrier. SiRNA-Keap1 (siKeap1) was loaded into mEXOs by sonication, and the obtained mEXOs-siKeap1 were found to promote HUVEC proliferation and migration while relieving oxidative stress in MGO-treated HUVECs. Meanwhile, in a mouse model of diabetic wounds, injection of mEXOs-siKeap1 significantly accelerated diabetic wound healing with enhanced collagen formation and neovascularization. Taken together, these data support the development of Keap1 knockdown as a potential therapeutic strategy for diabetic wounds and demonstrated the feasibility of mEXOs as a scalable, biocompatible, and cost-effective siRNA delivery system. Graphical Abstract The therapeutic effect of siKeap1-loaded mEXOs on diabetic wound healing was assessed. First, we found that the expression of Keap1 was upregulated in the wounds of diabetic mice and in human umbilical vein endothelial cells (HUVECs) pretreated with methylglyoxal (MGO). Next, we extracted exosomes from raw milk by differential centrifugation and loaded siKeap1 into milk-derived exosomes by sonication. The in vitro application of the synthetic complex (mEXOs-siKeap1) was found to increase the nuclear localization of Nrf2 and the expression of the antioxidant protein HO-1, thus reversing oxidative stress. Furthermore, in vivo mEXOs-siKeap1 administration significantly accelerated the healing rate of diabetic wounds (Scheme 1). Scheme 1 Schematic diagram. A Synthesis of mEXOs-siKeap1 complex. B Mechanism of mEXOs-siKeap1 in vitro. C The treatment effect of mEXOs-siKeap1 on an in vivo mouse model of diabetic wounds Supplementary Information The online version contains supplementary material available at 10.1007/s13346-023-01306-x.

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“…[38] Cow milk-derived exosomes and their cargo (especially miR-148a, miR-29b, miR-29c, miR-130a and TGF-𝛽) suppress 𝛽-cell differentiation and insulin secretion promoting mTORC1-dependent 𝛽-cell proliferation during the postnatal growth period of 𝛽-cells. [39] These studies suggest that milk exosomes can regulate mTOR through delivering miRNAs. The distinct regulatory bioactivities of HM exosomes from GDM and healthy parturient on mTOR is possibly attribute to the variety of miRNAs harbored in the exosomes.…”

Section: Discussionmentioning

confidence: 99%

Milk Exosomes from Gestational Diabetes Mellitus (GDM) and Healthy Parturient Exhibit Differential miRNAs Profiles and Distinct Regulatory Bioactivity on Hepatocyte Proliferation

Zheng

Lin

et al. 2023

Molecular Nutrition Food Res

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ScopeExosomes, a novel type of bioactive component in human milk (HM), affect infant development, growth, and health. Recent studies indicate that HM exosomes and miRNAs relate to gestational diabetes mellitus (GDM). However, the miRNAs profiles and functionalities of HM exosomes from GDM parturient remain unclear. This study aims to compare the differential miRNAs in HM exosomes from GDM and healthy parturient, and investigate the HM exosomes bioactivities in regulating hepatocyte proliferation and insulin sensitivity.Methods and ResultsThis study extracted HM exosomes from GDM (GDM‐EXO) and healthy (NOR‐EXO) parturient by ultracentrifugation, high‐throughput sequenced and compared the exosomal miRNAs profiles, and explored the regulatory bioactivities on hepatocyte proliferation in HepG2 cells and Balb/c mice. As compared to NOR‐EXO, GDM‐EXO has similar morphology, size, concentration, and exosome‐specific markers (CD9 and TSG101) expression. GDM‐EXO and NOR‐EXO specifically harbor 1299 and 8 miRNAs, respectively. Moreover, GDM‐EXO had 176 upregulated and 47 downregulated miRNAs compared with NOR‐EXO. Both GDM‐EXO and NOR‐EXO were absorbed in cultured HepG2 hepatocytes and mice liver. GDM‐EXO inhibited hepatocytes proliferation by downregulating mammalian target of rapamycin (mTOR) possibly via exosomal miR‐101‐3p delivery.ConclusionHM exosomes from GDM and healthy parturient exhibit differential miRNAs profiles and distinct regulatory bioactivity on hepatocyte proliferation.

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Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

Cited by 9 publications

References 570 publications

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

Milk-derived exosomes carrying siRNA-KEAP1 promote diabetic wound healing by improving oxidative stress

Milk Exosomes from Gestational Diabetes Mellitus (GDM) and Healthy Parturient Exhibit Differential miRNAs Profiles and Distinct Regulatory Bioactivity on Hepatocyte Proliferation

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