Biology subjects

Garcia, S. M.

Publications and source records attributed to Garcia, S. M..

4 recordsLinked to original sources

bioRxiv2025

Acid-Sensing Ion Channel 1a Deficiency Drives Endocrine Hypertension in Male Mice

BackgroundAcid-sensing ion channel 1a (ASIC1a) is an H+-gated cation channel that responds to extracellular acidosis in both normal and pathological states, including ischemia, inflammation, and metabolic disturbances. While ASIC1a regulates vascular reactivity, its role in blood pressure regulation remains unclear, particularly concerning sex, aging, and disease. This study aims to investigate whether ASIC1a: 1) contributes to cardiovascular function in a sex-dependent manner; 2) plays a dynamic role in cardiovascular homeostasis with aging; and 3) modulates the development of angiotensin II-induced systemic hypertension. MethodsRadiotelemeters were implanted in 6- and 18-month-old male and female wild-type (Asic1a+/+) and ASIC1a knockout (Asic1a-/-) mice to monitor mean arterial blood pressure and heart rate under baseline conditions and in response to angiotensin II. Blood gases, electrolytes, hormones, and end-organ injury were also assessed. ResultsAged male Asic1a-/- mice develop hypertension driven by aldosterone excess and sympathetic overactivity, which is accompanied by cardiac hypertrophy, aortic fibrosis, and glomerular hypertrophy. Female Asic1a-/- mice remain unaffected. In male Asic1a-/- mice, hyperaldosteronism occurs independent of the renin-angiotensin system and mitigates angiotensin II-induced hypertension. Furthermore, 6-month-old male Asic1a-/- mice exhibit elevated corticosterone, hypokalemia, reduced urine osmolality, increased pulse pressure, and cardiomyocyte hypertrophy that precedes hypertension. ConclusionsThese findings establish ASIC1a as a novel, sex-specific regulator of cardiovascular function, linking early corticosterone excess in male mice to hyperaldosteronism and implicating ASIC1a deficiency as a potential driver of endocrine-related hypertension. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/645371v2_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@145dcf0org.highwire.dtl.DTLVardef@1ac468eorg.highwire.dtl.DTLVardef@14c4ad5org.highwire.dtl.DTLVardef@1c4fd2e_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

Distinct human stem cell subpopulations drive adipogenesis and fibrosis in musculoskeletal injury

Fibroadipogenic progenitors (FAPs) maintain healthy skeletal muscle in homeostasis but drive muscle degeneration in chronic injuries by promoting adipogenesis and fibrosis. To uncover how these stem cells switch from a pro-regenerative to pro-degenerative role we perform single-cell mRNA sequencing of human FAPs from healthy and injured human muscles across a spectrum of injury, focusing on rotator cuff tears. We identify multiple subpopulations with progenitor, adipogenic, or fibrogenic gene signatures. We utilize full spectrum flow cytometry to identify distinct FAP subpopulations based on highly multiplexed protein expression. Injury severity increases adipogenic commitment of FAP subpopulations and is driven by the downregulation of DLK1. Treatment of FAPs both in vitro and in vivo with DLK1 reduces adipogenesis and fatty infiltration, suggesting that during injury, reduced DLK1 within a subpopulation of FAPs may drive degeneration. This work highlights how stem cells perform varied functions depending on tissue context, by dynamically regulating subpopulation fate commitment, which can be targeted improve patient outcomes after injury.

cell biology↗

bioRxiv2021

ACVR1R206H increases osteogenic/ECM gene expression and impairs myofiber formation in human skeletal muscle stem cells

Abnormalities in skeletal muscle repair lead to poor function and complications such as scarring or heterotopic ossification (HO). Here, we use fibrodysplasia ossificans progressiva (FOP), a disease of progressive HO caused by ACVR1R206H (Activin receptor type-1 receptor) mutation, to elucidate how ACVR1 affects skeletal muscle repair. Rare and unique primary FOP human muscle stem cells (Hu-MuSCs) isolated from cadaveric skeletal muscle demonstrated increased ECM marker expression, and showed skeletal muscle-specific impaired engraftment and regeneration ability. Human induced pluripotent stem cell (iPSC)-derived muscle stem/progenitor cells (iMPCs) Single cell transcriptome analyses from FOP also revealed unusually increased ECM and osteogenic marker expression compared to control iMPCs. These results show that iMPCs can recapitulate many aspects of Hu-MuSCs for detailed in vitro study, that ACVR1 is a key regulator of Hu-MuSC function and skeletal muscle repair; and that ACVR1 activation in iMPCs or Hu-MuSCs contributes to HO by changing the local tissue environment.

cell biology↗

bioRxiv2017

Using Barcoded Zika Virus to Assess virus Population Structure in vitro and in Aedes aegypti Mosquitoes

Arboviruses such as Zika virus (ZIKV, Flaviviridae; Flavivirus) replicate in both mammalian and insect hosts where they encounter a variety of distinct host defenses. To overcome these pressures, arboviruses exist as diverse populations of distinct genomes. However, transmission between hosts and replication within hosts can involve genetic bottlenecks, during which population size and viral diversity may be significantly reduced, potentially resulting in large fitness losses. Understanding the points at which bottlenecks exist during arbovirus transmission is critical to identifying targets for preventing transmission. To study these bottleneck effects, we constructed 4 \"barcoded\" ZIKV clones - 2 with an 8-base-pair degenerate insertion in the 3 UTR and 2 with 8 or 9 degenerate synonymous changes in the coding sequence, theoretically containing thousands of variants each. We passaged these viruses 3 times each in 2 mammalian and 2 mosquito cell lines and characterized selection of the \"barcode\" populations using deep sequencing. Additionally, the viruses were used to feed three recently field-caught populations of Aedes aegypti mosquitoes to assess bottlenecks in a natural host. The barcoded viruses replicated well in multiple cell lines in vitro and in vivo in mosquitoes and could be characterized using next-generation sequencing. The stochastic nature of mosquito transmission was clearly shown by tracking individual barcodes in Ae. aegypti mosquitoes. Barcoded viruses provide an efficient method to examine bottlenecks during virus infection.\n\nAUTHOR SUMMARYIn general, mosquito-borne viruses like ZIKV must replicate in two very different host environments: an insect and a mammalian host. RNA viruses such as ZIKV must maintain genetic diversity in order to adapt to these changing conditions. During this transmission cycle, several barriers exist which can severely restrict viral genetic diversity, causing bottlenecks in the virus population. It is critical to understand these bottlenecks during virus transmission as this will provide important insights into the selective forces shaping arbovirus evolution within and between hots. Here, we employ a set of barcoded ZIKV constructs containing a degenerate stretch of nucleotides that can be tracked using next-generation sequencing. We found that the insertion site in the genome was an important determinant of the resulting diversity of the genetic barcode. We also found that bottlenecks varied between different mosquito populations and patterns of genetic diversity were distinct among individual mosquitoes within a single population, highlighting the randomness of virus dissemination in mosquitoes. Our study characterizes a new tool for tracking bottlenecks during virus transmission in vivo and highlights the importance of both viral and host factors on the maintenance of viral diversity.

molecular biology↗