Biology subjects

Mateus Goncalves, L.

Publications and source records attributed to Mateus Goncalves, L..

4 recordsLinked to original sources

bioRxiv2026

Vascular Destabilization and Pericyte Detachment are Mediated by hIAPP Aggregation in Transgenic Mice.

Aims/hypothesisHuman islet amyloid polypeptide (hIAPP) deposition is a common feature of type-2 diabetes (T2D). Previous studies have demonstrated hIAPP-mediated endothelial cell (EC) dysfunction and inflammation, but little is known about islet microvascular stability or pericyte function in hIAPP-containing islets. This study investigates how islet endothelial cells and pericytes are influenced by hIAPP aggregation. MethodsBulk RNAseq and qPCR were conducted on hIAPP or vehicle treated MS-1 cells and bead-purified human islet CD31+ cells from donors with or without T2D to determine how islet ECs respond to hIAPP exposure. Confocal imaging of living pancreatic slices obtained from hIAPP transgenic mice was conducted to evaluate the effect of hIAPP deposition on islet pericyte function and vasomotor responses. ResultshIAPP-treated MS-1 cells and ECs purified from T2D islets demonstrate downregulation of leading-edge genes associated with extracellular matrix and cell adhesion pathways. Pericytes from hIAPP-expressing mouse islets appear detached from underlying endothelial cells, which was associated with impaired vasomotor responses to constrictive or dilatory stimuli. Conclusions/interpretationhIAPP induces vascular destabilization by downregulating mRNA of key extracellular matrix and cell adhesion molecules in ECs, likely promoting the breakdown of EC-EC and EC-pericyte coupling. hIAPP disrupts EC-pericyte connections, and pericyte detachment ultimately impairs pericytes ability to modulate capillary diameter without impairing intracellular Ca2+ dynamics. Our data suggest that amyloid deposition compromises EC health and survival by altering islet microvascular morphology, stability, and function. This, in turn, may disrupt islet microvascular stability and exacerbate endocrine cell dysfunction in T2D. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABS- hIAPP is cytotoxic to islet endothelial cells and beta cells, and contributes to islet failure in type-2 diabetes (T2D) - hIAPP transgenic mice demonstrate islet capillary dilation, loss of vascular structures, and increased pericyte density - Impaired pericyte anchorage and vascular fragmentation drive diabetes-related vasculopathies in other tissues, like the retina, kidney, and brain What is the key question?- How does the surviving microvasculature in islets respond to hIAPP deposition? What are the new findings?- Endothelial cells demonstrate transcriptional downregulation of key genes involved in cytoskeleton, ECM, and cell-adhesion maintenance, including Thbs1, Tln1, and Plec. - Amyloid deposits disrupt homeostatic interactions between endothelial cells and pericytes. - Amyloid-adjacent islet pericytes are detached from endothelial cells and display impaired ability to modulate capillary diameter. How might this impact on clinical practice in the foreseeable future?- Therapies targeting endothelial cell-pericyte interactions may restore islet microvascular stability and improve islet function, especially in the context of early T2D.

molecular biology↗

bioRxiv2025

Post-Inhibitory Rebound by δ-Cells Transforms Inhibition into Excitationand Redefines Islet Plasticity.

The coordination of hormone secretion within the pancreatic islet remains incompletely understood. Here we identify post-inhibitory rebound (PIR), a transient excitatory overshoot of glucoregulatory hormones following inhibitory signaling, as a fundamental and previously unrecognized feature of islet physiology. Human islets from donors with type 2 diabetes displayed concomitantly elevated insulin and somatostatin secretion with tightly correlated dynamics, a pattern reproduced in islets from high-fat-diet-fed mice. Using a combination of cell-type-specific chemogenetic and optogenetic approaches, high-resolution triple-hormone perifusion, Ca{superscript 2} imaging, in vivo islet grafts, and physiological ligands, we demonstrate that transient {delta}-cell activation or inhibition consistently triggers rebound excitation of {beta}- and -cells. These responses generate glucose-dependent, synchronized oscillations of insulin and glucagon secretion that are partially mediated by somatostatin receptor signaling. Mechanistic insights obtained in mouse islets were recapitulated using translatable approaches in human islets, establishing the relevance of this dynamic signaling framework across species. In vivo, selective {delta}-cell modulation bidirectionally regulated systemic glucose tolerance, confirming {delta}-cell control over endocrine output. These findings support a model in which somatostatin signaling encodes hormone output through temporal dynamics rather than tonic inhibition. By reframing somatostatin as a dynamic regulator of excitability, we identify {delta}-cell-driven rebound as a mechanism that converts inhibition into coordinated endocrine output. Together, this work establishes a revised framework for intra-islet paracrine crosstalk in which temporal dynamics, rather than static inhibition, govern endocrine coordination. Significance StatementHormone secretion in the pancreatic islet has long been explained by inhibitory feedback loops, with somatostatin viewed as a static suppressor of insulin and glucagon release. Our study overturns this paradigm by identifying post-inhibitory rebound (PIR) as a dynamic property of intra-islet signaling. {delta}-cell-driven PIR synchronizes - and {beta}-cell activity, enabling adaptive, glucose-dependent hormone release and revealing that somatostatin confers system plasticity when needed. This work establishes a revised model of intra-islet paracrine crosstalk in which {delta}-cell-driven rebound dynamics, rather than static inhibition, determine endocrine coordination and system plasticity. Our discovery reframes inhibition as a rhythmic and regenerative force, positioning PIR as a potentially generalizable mechanism of excitability across biological systems. HighlightsO_LI{delta}-cells convert inhibition into excitation. Transient somatostatin signals trigger post-inhibitory rebound (PIR) in {beta}- and -cells, generating glucose-dependent synchronized hormone oscillations. C_LIO_LIProvides a mechanistic explanation for a long-standing paradox in human type 2 diabetes. Elevated basal insulin and somatostatin secretion are positively correlated; PIR explains this co-hypersecretion. C_LIO_LIAsymmetric {delta}-cell control confers islet plasticity. Stronger inhibition of -cells versus {beta}-cells enables balanced insulin/glucagon output during feeding or glucagon-skewed surges for hypoglycemia protection. C_LIO_LIMulti-scale validation across species. Chemogenetics, optogenetics, native ligands, Ca{superscript 2} imaging, in vivo grafts, and a data-informed phenomenological model demonstrate conservation from mouse to human islets. C_LIO_LIInhibition is instructive. A revised model of intra-islet paracrine crosstalk in which cell-type-specific temporal dynamics encode hormone output through rebound. C_LI Graphical AbstractSomatostatin, long considered a static inhibitor of growth and secretion, instead acts as a dynamic modulator that transforms inhibition into robust, context-dependent excitation. In the islet, amplified SST pulses drive rebound excitation to promote balanced insulin and glucagon output during anabolic demand, while dampening produces glucagon-skewed surges for protection against hypoglycemia. Inhibition in the islet is not merely suppressive but instructive, encoding future hormone output through rebound dynamics. The same pulse-rebound principle may operate in SST-rich systems such as the brain, gut, and tumors, where dynamic modulation of SST signaling confers adaptability and robustness rather than tonic suppression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/687745v2_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1a88336org.highwire.dtl.DTLVardef@3e618aorg.highwire.dtl.DTLVardef@175d94forg.highwire.dtl.DTLVardef@decf4_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Microvascular homeostasis is compromised in pancreatic islets in a mouse model of beta cell loss and low-grade inflammation

Vascular dysfunction is considered a consequence of diabetes. However, in pancreatic islets, some haemodynamic changes occur before the onset of symptoms. The underlying mechanisms driving islet vascular abnormalities have not been fully characterized, but islet pericyte dysfunction appears to be an early event in the pathogenesis of human type 1 diabetes (T1D). It remains to be investigated, however, how abnormal pericyte physiology affects their ability to regulate islet blood flow and vascular permeability. To address this issue, we treated mice with multiple subdiabetogenic doses of the beta cell toxin streptozotocin (STZ; 50mg/kg) and recorded islet vascular responses when animals developed glucose intolerance but were still not diabetic (average fed glycemia <200 mg/dL). At this stage, accompanying increased macrophage density, islet pericytes adopted a myofibroblast-like appearance and interacted closely with endothelial cells expressing high levels of the adhesion molecule ICAM-1. This phenotypical switch of pericytes in STZ-treated mice had functional repercussions: it impacted glucose-induced vasomotor responses ex vivo in living pancreas slices and hyperglycemia-stimulated increases in islet blood flow recorded in vivo in the exteriorized pancreas. Impaired vasomotor responses were accompanied by enhanced extravazation of a fluorescent dextran (500 kDa) from vessels and accumulation in the interstitial space surrounding islets in STZ-treated mice. Our study indicates that abnormal pericyte function, and compromised capacity to regulate blood flow and vascular integrity, are part of a pathogenic process occurring in islets before diabetes onset, associated with a loss of functional beta cell mass and inflammation. Article highlightsO_LIFunctional and morphological alterations of islet capillaries occur in mice early after multiple low dose STZ treatment; C_LIO_LIIslet pericytes remodel and express higher levels of the myofibroblast marker periostin upon STZ treatment; C_LIO_LIIslet pericyte cytosolic Ca2+ and vasomotor responses to high glucose are impaired in living pancreas slices from mice treated with STZ; C_LIO_LIIslet hyperemic responses to increases in glycemia recorded in the exteriorized pancreas are abolished in STZ-treated mice; C_LIO_LIVascular alterations are associated with a pro-inflammatory environment as islets from STZ-treated mice have more macrophages, an inflamed and leaky endothelium. C_LI

physiology↗

bioRxiv2023

Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes

Pancreatic islets are endocrine organs that depend on their microvasculature to function properly. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here we investigated islet pericyte density, phenotype and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (Aab+; all GADA+) and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes towards pro-fibrotic myofibroblasts. Using publicly available RNAseq data, we further found that transcriptional alterations related to endothelin-1 signaling, vascular and ECM remodeling are hallmarks of single Aab+ donor pancreata. Our data show that islet pericyte/microvascular dysfunction is present at early stages of islet autoimmunity. HighlightsO_LIChanges in islet pericyte coverage and phenotype occur during T1D progression. C_LIO_LIVascular responses to vasoactive stimuli are impaired in islets from Aab+ and T1D donors. C_LIO_LIEndothelin-1 action and receptor expression are altered in vascular cells from Aab+ and T1D donors. C_LIO_LIStrong vascular remodeling occurs in the pancreas of Aab+ and T1D donors. C_LI

physiology↗