Biology subjects

Aldana, B.

Publications and source records attributed to Aldana, B..

3 recordsLinked to original sources

bioRxiv2024

Restoring oxidative phosphorylation enhances osteogenesis in mitochondrial DNA translation defective human bone marrow stromal cells

Bone formation is critical to maintain bone integrity. Here, we studied the importance of intact energy metabolism for bone formation in humans. The skeletal impact of impaired oxidative phosphorylation (OXPHOS) was investigated in adult individuals with genetically defective mitochondrial DNA translation (m.3243A>G). Although impaired mitochondrial ATP production in m.3243A>G human bone marrow stromal cells (hBMSC) was compensated by increased glycolytic ATP production (unchanged net ATP production), both in vitro osteoblast differentiation and in vivo ectopic bone formation were decreased. The impaired OXPHOS was associated with mitochondrial stress and disruption of the pro-osteogenic transcriptional program characteristic of hBMSC. Supporting OXPHOS pharmacologically in hBMSC restored mitochondrial ATP production, their transcriptional program and metabolism, leading to upregulation of osteogenic genes and restoration of bone formation capacity. These findings demonstrate a mitochondrial regulation mechanism of the osteogenic capacity of hBMSCs and identify OXPHOS as a potential target for increasing bone formation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/629993v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@fca817org.highwire.dtl.DTLVardef@17fb2d3org.highwire.dtl.DTLVardef@b5667forg.highwire.dtl.DTLVardef@15c35db_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Microgliosis driven by palmitate exposure alters energy metabolism and extracellular vesicles release that impact behavior and systemic metabolism

Dietary patterns that include an excess of foods rich in saturated fat are associated with brain dysfunction. Although microgliosis has been proposed to play a key role in the development of brain dysfunction in diet-induced obesity (DIO), neuroinflammation with cytokine over-expression is often not always observed. Thus, mechanisms by which microglia contribute to brain impairment in DIO are uncertain. Using the BV2 cell model, we investigated the gliosis profile of microglia exposed to palmitate (200 {micro}mol/L), a saturated fatty acid abundant in high-fat diet and in the brain of obese individuals. We observed that microglia respond to a 24-hour palmitate exposure with increased proliferation, and with a metabolic network rearrangement that favors energy production from glycolysis rather than oxidative metabolism, despite stimulated mitochondria biogenesis. In addition, while palmitate did not induce increased cytokine expression, it modified the protein cargo of released extracellular vesicles (EVs). When administered intra-cerebroventricularly to mice, EVs from palmitate-exposed microglia in vitro led to memory impairment, depression-like behavior, and glucose intolerance, when compared to mice receiving EVs from vehicle-treated microglia. We conclude that microglia exposed to palmitate can mediate brain dysfunction through the cargo of shed EVs.

neuroscience↗

bioRxiv2022

Micropatterned Organoids Enable Modeling of the Earliest Stages of Human Cardiac Vascularization

Although model organisms have provided insight into the earliest stages of cardiac vascularization, we know very little about this process in humans. Here we show that spatially micropatterned human pluripotent stem cells (hPSCs) enable in vitro modeling of this process, corresponding to the first three weeks of in vivo human development. Using four hPSC fluorescent reporter lines, we create cardiac vascular organoids (cVOs) by identifying conditions that simultaneously give rise to spatially organized and branched vascular networks within endocardial, myocardial, and epicardial cells. Using single-cell transcriptomics, we show that the cellular composition of cVOs resembles that of a 6.5 post-conception week (PCW) human heart. We find that NOTCH and BMP pathways are upregulated in cVOs, and their inhibition disrupts vascularization. Finally, using the same vascular-inducing factors to create cVOs, we produce hepatic vascular organoids (hVOs). This suggests there is a conserved developmental program for creating vasculature within different organ systems. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/499233v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@17b265org.highwire.dtl.DTLVardef@1c1113eorg.highwire.dtl.DTLVardef@531c18org.highwire.dtl.DTLVardef@596bd2_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗