Publications by authors named "Matthew Riccetti"

5 Publications

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Resident interstitial lung fibroblasts and their role in alveolar stem cell niche development, homeostasis, injury, and regeneration.

Stem Cells Transl Med 2021 Feb 24. Epub 2021 Feb 24.

The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix-, myo-, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix-, myo-, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.
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http://dx.doi.org/10.1002/sctm.20-0526DOI Listing
February 2021

mTOR-driven neural circuit changes initiate an epileptogenic cascade.

Prog Neurobiol 2021 May 9;200:101974. Epub 2020 Dec 9.

Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States; Center for Pediatric Neuroscience, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States; Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States; Department of Anesthesia, University of Cincinnati, Cincinnati, OH, 45267, United States. Electronic address:

Mutations in genes regulating mTOR pathway signaling are now recognized as a significant cause of epilepsy. Interestingly, these mTORopathies are often caused by somatic mutations, affecting variable numbers of neurons. To better understand how this variability affects disease phenotype, we developed a mouse model in which the mTOR pathway inhibitor Pten can be deleted from 0 to 40 % of hippocampal granule cells. In vivo, low numbers of knockout cells caused focal seizures, while higher numbers led to generalized seizures. Generalized seizures coincided with the loss of local circuit interneurons. In hippocampal slices, low knockout cell loads produced abrupt reductions in population spike threshold, while spontaneous excitatory postsynaptic currents and circuit level recurrent activity increased gradually with rising knockout cell load. Findings demonstrate that knockout cells load is a critical variable regulating disease phenotype, progressing from subclinical circuit abnormalities to electrobehavioral seizures with secondary involvement of downstream neuronal populations.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026598PMC
May 2021

The elephant in the lung: Integrating lineage-tracing, molecular markers, and single cell sequencing data to identify distinct fibroblast populations during lung development and regeneration.

Matrix Biol 2020 09 19;91-92:51-74. Epub 2020 May 19.

The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Molecular and Developmental Biology Graduate Program, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH, United States. Electronic address:

During lung development, the mesenchyme and epithelium are dependent on each other for instructive morphogenic cues that direct proliferation, cellular differentiation and organogenesis. Specification of epithelial and mesenchymal cell lineages occurs in parallel, forming cellular subtypes that guide the formation of both transitional developmental structures and the permanent architecture of the adult lung. While epithelial cell types and lineages have been relatively well-defined in recent years, the definition of mesenchymal cell types and lineage relationships has been more challenging. Transgenic mouse lines with permanent and inducible lineage tracers have been instrumental in identifying lineage relationships among epithelial progenitor cells and their differentiation into distinct airway and alveolar epithelial cells. Lineage tracing experiments with reporter mice used to identify fibroblast progenitors and their lineage trajectories have been limited by the number of cell specific genes and the developmental timepoint when the lineage trace was activated. In this review, we discuss major developmental mesenchymal lineages, focusing on time of origin, major cell type, and other lineage derivatives, as well as the transgenic tools used to find and define them. We describe lung fibroblasts using function, location, and molecular markers in order to compare and contrast cells with similar functions. The temporal and cell-type specific expression of fourteen "fibroblast lineage" genes were identified in single-cell RNA-sequencing data from LungMAP in the LGEA database. Using these lineage signature genes as guides, we clustered murine lung fibroblast populations from embryonic day 16.5 to postnatal day 28 (E16.5-PN28) and generated heatmaps to illustrate expression of transcription factors, signaling receptors and ligands in a temporal and population specific manner.
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http://dx.doi.org/10.1016/j.matbio.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434667PMC
September 2020

A Positive Feedback Loop of Hippo- and c-Jun-Amino-Terminal Kinase Signaling Pathways Regulates Amyloid-Beta-Mediated Neurodegeneration.

Front Cell Dev Biol 2020 13;8:117. Epub 2020 Mar 13.

Department of Biology, University of Dayton, Dayton, OH, United States.

Alzheimer's disease (AD, OMIM: 104300) is an age-related disorder that affects millions of people. One of the underlying causes of AD is generation of hydrophobic amyloid-beta 42 (Aβ42) peptides that accumulate to form amyloid plaques. These plaques induce oxidative stress and aberrant signaling, which result in the death of neurons and other pathologies linked to neurodegeneration. We have developed a eye model of AD by targeted misexpression of human Aβ42 in the differentiating retinal neurons, where an accumulation of Aβ42 triggers a characteristic neurodegenerative phenotype. In a forward deficiency screen to look for genetic modifiers, we identified a molecularly defined deficiency, which suppresses Aβ42-mediated neurodegeneration. This deficiency uncovers () gene, a member of evolutionarily conserved Hippo signaling pathway that regulates growth. Activation of Hippo signaling causes cell death, whereas downregulation of Hippo signaling triggers cell proliferation. We found that Hippo signaling is activated in Aβ42-mediated neurodegeneration. Downregulation of Hippo signaling rescues the Aβ42-mediated neurodegeneration, whereas upregulation of Hippo signaling enhances the Aβ42-mediated neurodegeneration phenotypes. It is known that c-Jun-amino-terminal kinase (JNK) signaling pathway is upregulated in AD. We found that activation of JNK signaling enhances the Aβ42-mediated neurodegeneration, whereas downregulation of JNK signaling rescues the Aβ42-mediated neurodegeneration. We tested the nature of interactions between Hippo signaling and JNK signaling in Aβ42-mediated neurodegeneration using genetic epistasis approach. Our data suggest that Hippo signaling and JNK signaling, two independent signaling pathways, act synergistically upon accumulation of Aβ42 plaques to trigger cell death. Our studies demonstrate a novel role of Hippo signaling pathway in Aβ42-mediated neurodegeneration.
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http://dx.doi.org/10.3389/fcell.2020.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082232PMC
March 2020

Alzheimer's disease: the silver tsunami of the 21(st) century.

Neural Regen Res 2016 May;11(5):693-7

Department of Biology, University of Dayton, Dayton, OH, USA; Premedical Program, University of Dayton, Dayton, OH, USA; Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA.

Alzheimer's disease (AD), a fatal progressive neurodegenerative disorder, has no cure to date. One of the causes of AD is the accumulation of amyloid-beta 42 (Aβ42) plaques, which result in the onset of neurodegeneration. It is not known how these plaques trigger the onset of neurodegeneration. There are several animal models developed to (i) study etiology of disease, (ii) look for genetic modifiers, and (iii) identify chemical inhibitors that can block neurodegeneration and help to find cure for this disease. An insect model of Drosophila melanogaster has also provided new insights into the disease. Here we will discuss the utility of the Drosophila eye model to study Alzheimer's disease.
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http://dx.doi.org/10.4103/1673-5374.182680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904444PMC
May 2016