Background: Mesenchymal stem cells (MSCs) derived from gestational tissues offer a promising avenue for prenatal intervention in congenital malformations although their application is hampered by concerns related to cellular plasticity and the need for invasive, high-risk surgical procedures. Here, we present naturally occurring exosomes (EXOs) isolated from amniotic fluid-derived MSCs (AF-MSCs) and their mimetic analogs (MIMs) as viable, reproducible, and stable alternatives. These nanovesicles present a minimally invasive therapeutic option, addressing the limitations of MSC-based treatments while retaining therapeutic efficacy.
Methods: MIMs were generated from AF-MSCs by combining sequential filtration steps through filter membranes with different porosity and size exclusion chromatography columns. A physicochemical, structural, and molecular comparison was conducted with exosomes (EXOs) released from the same batch of cells. Additionally, their distribution patterns in female mice were evaluated following in vivo administration, along with an assessment of their safety profile throughout gestation in a mouse strain predisposed to neural tube defects (NTDs). The possibility to exploit both formulations as mRNA-therapeutics was explored by evaluating cell uptake in two different cell types(fibroblasts, and macrophages) and mRNA functionality overtime in an in vitro experimental setting as well as in an ex vivo, whole embryo culture using pregnant C57BL6 dams.
Results: Molecular and physiochemical characterization showed no differences between EXOs and MIMs, with MIMs determining a threefold greater yield. Biodistribution patterns following intraperitoneal administration were comparable between the two particle types, with the uterus being among targeted organs. No toxic effects were observed in the dams during gestation, nor were there any malformations or significant differences in the number of viable versus dead fetuses detected. MIMs delivered a more intense and prolonged expression of mRNA encoding for green fluorescent protein in macrophages and fibroblasts. An ex-vivo whole embryo culture demonstrated that MIMs mainly accumulate at the level of the yolk sac, while EXOs reach the embryo.
Conclusions: The present data confirms the potential application of EXOs and MIMs as suitable tools for prevention and treatment of NTDs and proposes MIMs as prospective vehicles to prevent congenital malformations caused by in utero exposure to drugs.
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http://dx.doi.org/10.1186/s13287-024-04082-8 | DOI Listing |
Am J Med Genet A
December 2024
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Diamond Blackfan anemia (DBA) is an autosomal dominant disorder with a heterogeneous clinical presentation which may include macrocytic anemia typically presenting in the first year of life, growth retardation, and congenital malformations in 30%-50% of patients. This phenotypic variability is partially explained by genotype-phenotype correlations, with several ribosomal protein genes implicated in this disorder. Most cases are due to de novo variants, but familial occurrences highlight variable expressivity and reduced penetrance.
View Article and Find Full Text PDFBrain Res
December 2024
Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Congenital Zika Syndrome (CZS) is a condition that arises when a neonate presents with abnormalities resulting from Zika virus infection during gestation. While microcephaly is a prominent feature of the syndrome, other forms of brain damage are also observed, often accompanied by significant neurological complications. It is therefore essential to investigate the long-term effects of CZS, with special attention to sex differences, particularly concerning hippocampal function, given its vulnerability to viral infections.
View Article and Find Full Text PDFAm J Intellect Dev Disabil
January 2025
Carly Hyde, University of California, Los Angeles; Logan Shurtz, University of Texas Southwestern Medical Center; Nicole McDonald, University of California, Los Angeles; Maria Pizzano, Loyola Marymount University; Charles A. Nelson, Boston Children's Hospital and Harvard Medical School; Elizabeth A. Thiele, Massachusetts General Hospital; Connie Kasari, University of California, Los Angeles; and Shafali Jeste, Children's Hospital Los Angeles.
Tuberous sclerosis complex (TSC) is a genetic condition characterized by both medical and neuropsychiatric diagnoses that emerge across the lifespan. As part of a clinical trial, caregivers of children with TSC were interviewed about their experiences navigating medical, school, and social services. Semistructured interviews (N = 20) with caregivers of children with TSC (27-60 months) were conducted upon exit from the study.
View Article and Find Full Text PDFEur J Pediatr
December 2024
Dept. of Research and Development, SeysCentra, Malden, The Netherlands.
Unlabelled: Children with Noonan syndrome-like RASopathies are at increased risk for developing feeding problems due to comorbid organic impairments at an early age, such as gastrointestinal problems or other organicity. Their feeding problems can ultimately often be classified as avoidant/restrictive food intake disorder, for which behavioral therapy is the first-choice treatment. The research question in this study is whether this treatment leads to similar results as in children without these RASopathies.
View Article and Find Full Text PDFArch Womens Ment Health
December 2024
College of Pharmacy, Jinan University, Guangzhou, Guangdong, China.
Purpose: This study investigates the potential association between commonly prescribed psychotropic medications, such as Atypical Antipsychotics (AAs), Selective Serotonin Reuptake Inhibitors (SSRIs), and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs), and congenital anomalies in newborns. The analysis uses data from the Food and Drug Administration Adverse Event Reporting System (FAERS).
Methods: Spontaneously reported cases of congenital anomalies in newborns (under 28 days old) were extracted from the FAERS database, covering January 2004 to June 2023.
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