American Journal Of Physiology. Cell Physiology[JOURNAL]
Sun
200 papers
Beyond thrombosis: the role of platelets in cardiovascular, oncological, and immune-related inflammatory diseases.
Jiang W, Tang WH, Zhang Y
Am J Physiol Cell Physiol · 2026 Jul · PMID 41944650 · Publisher ↗
Platelets are anucleate cells derived from megakaryocytes that play a vital role in hemostasis through glycoprotein-mediated adhesion and coagulation. Their pathophysiological functions extend across cardiovascular, onco...
Platelets are anucleate cells derived from megakaryocytes that play a vital role in hemostasis through glycoprotein-mediated adhesion and coagulation. Their pathophysiological functions extend across cardiovascular, oncological, and inflammatory disorders. In cardiovascular diseases, activated platelets interact with endothelial and smooth muscle cells by delivering inflammatory mediators and microRNAs, thereby modulating vascular remodeling. In addition, tumor-educated platelets facilitate metastasis by transferring mitochondria via tunneling nanotubes, expressing immune checkpoint molecules such as programmed death-ligand 1, and releasing angiogenic factors like vascular endothelial growth factor. Furthermore, platelets coordinate immune responses through receptor-mediated signaling and the release of cytokines, as well as factors that induce neutrophil extracellular traps. Emerging single-cell proteomic and transcriptomic analyses have identified disease-specific signaling components in platelets, revealing potential diagnostic and therapeutic targets for platelet-associated diseases. This review highlights recent advancements on the pathophysiological roles of platelets and their therapeutic implications in cardiovascular, oncological, and immune-related inflammatory diseases.
Correction for Du et al., volume 310, 2016, p. C270-C283.
Am J Physiol Cell Physiol · 2026 Apr · PMID 41941567 · Publisher ↗
Abstract loading — click title to view on PubMed.
Mitochondrial localization around central nuclei in regenerating skeletal muscle following eccentric contraction in rat model.
Murakami R, Tabuchi A, Kobayashi T … +4 more , Yagishita K, Hoshino D, Poole DC, Kano Y
Am J Physiol Cell Physiol · 2026 May · PMID 41931399 · Publisher ↗
This study aimed to characterize the spatial distribution and ultrastructural changes of mitochondria in regenerating muscle following eccentric contractions (ECC)-induced injury, utilizing photothermal microscopy (PTM)...
This study aimed to characterize the spatial distribution and ultrastructural changes of mitochondria in regenerating muscle following eccentric contractions (ECC)-induced injury, utilizing photothermal microscopy (PTM) and transmission electron microscopy (TEM). ECC was applied to the gastrocnemius muscles of male rats (13 wk old, 284.8 ± 8.9 g), and regenerating muscles were harvested 7 days post injury. PTM, featuring a high-sensitivity optical system, was used to visualize the wide-range and three-dimensional distribution of mitochondria within the white gastrocnemius muscle region. Concurrently, TEM was used for quantitative analysis of mitochondrial ultrastructural morphology, including cristae density. In regenerating muscle, the regular lattice-like network observed in normal tissue was disrupted and replaced by fragmented, randomly distributed mitochondria. Notably, both PTM and TEM analyses revealed a high concentration of mitochondria specifically around "central nuclei," a hallmark of regenerating muscle (i.e., within 0.1-1.0 µm: normal 1.8 ± 2.0% vs. regeneration 5.5 ± 3.6%, < 0.0001, by TEM data). Detailed morphological analysis further demonstrated that mitochondria in the immediate vicinity of the central nucleus (<0.1 µm) had significantly lower cristae density (inner and outer membranes ratio, 1.10 ± 0.43) compared with those in distal regions (>2.0 µm) (1.80 ± 0.65, < 0.0001), indicating that they may be structurally immature. In conclusion, during the muscle regeneration process, mitochondria specifically localize around the central nucleus. Given their low cristae density, these potentially represent newly synthesized (biogenesis-derived) mitochondria. This perinuclear accumulation is thought to function as a critical energy source for the nuclear transcriptional and translational activities required for muscle differentiation while also serving as a hub for organelle coordination during the regeneration process. Using PTM and TEM, this study reveals that mitochondrial networks fragment and cluster around central nuclei during muscle regeneration. These perinuclear mitochondria are structurally immature, exhibiting low cristae density. This localization suggests a potential bioenergetic hub that may support the transcriptional and translational demands of muscle differentiation. Thus, this accumulation likely plays a key role in metabolic and organelle coordination during functional muscle repair.
Complement activation beyond the traditional cascades: extracellular to intracellular signaling network.
Zhang T, Min X, Wu Y … +1 more , Li K
Am J Physiol Cell Physiol · 2026 May · PMID 41926626 · Publisher ↗
The complement system, as an evolutionarily conserved arm of innate immunity, plays pivotal roles in diverse pathophysiological processes, including homeostasis maintenance, cellular metabolism modulation, and inflammato...
The complement system, as an evolutionarily conserved arm of innate immunity, plays pivotal roles in diverse pathophysiological processes, including homeostasis maintenance, cellular metabolism modulation, and inflammatory regulation. Although traditional activation pathways are well-characterized, growing evidence has revealed noncanonical complement activation mechanisms. These include cross talk with intravascular coagulation, kinin, and fibrinolytic cascades, proteases leaking into the interstitium, hypochlorite or oxygen radicals, and even intracellular activation pathways or membrane-anchored serine proteases, highlighting unprecedented complexity in complement biology. This review comprehensively summarizes the proteases involved in these processes and their potential pathophysiological functions. However, the physiological importance of these pathways requires further investigation, especially regarding whether coagulation, kinin, and fibrinolytic enzymes can functionally activate complement in vivo, and the cell- and context-specific mechanisms that regulate intracellular complement activation, as well as the dynamic integration of traditional and noncanonical complement activation pathways under various challenges. Future investigations should integrate multiomics, super-resolution imaging, and gene editing tools to discriminate physiological regulation from pathological "noise," ultimately advancing precise targeted complement therapeutics.
Fibroblast specialization across microanatomy in a single-cell atlas of human Achilles tendon.
Cohen CJ, Mimpen JY, Kurjan A … +20 more , Paul C, Sharma S, Ramos-Mucci L, Ikwuanusi CT, Aksu AC, Boakye Serebour T, Nikolic M, Rue-Albrecht K, Gibbons C, Whitwell D, Cosker T, Gwilym S, Siddiqi A, Rajasekaran RB, Branford-White H, Cribbs AP, Hulley PA, Sims D, Baldwin MJ, Snelling SJB
Am J Physiol Cell Physiol · 2026 May · PMID 41920776 · Publisher ↗
Tendons are transitional tissues linking muscle to bone, enabling locomotion and fine motor control. The cellular biology across the Achilles tendon unit is poorly understood, yet is critical for interpreting normal func...
Tendons are transitional tissues linking muscle to bone, enabling locomotion and fine motor control. The cellular biology across the Achilles tendon unit is poorly understood, yet is critical for interpreting normal function and pathological changes across its microanatomically defined functional zones. We generated a spatially resolved transcriptomic atlas of adult (age 45-76) nontendinopathic human Achilles tendon, sampling the tendon-bone junction (enthesis), midbody, myotendinous junction, and adjoining muscle. Six fibroblast subtypes were identified, with distinct transcriptional profiles and spatial distributions, suggesting specialized functional roles across the tendon. Two dominant fibroblast types were specifically positioned in the tendon midsubstance and paratenon (vessel-rich region surrounding the tendon fibrils); other populations included perineural, myotendinous junction-specific, muscle-specific, and lining-layer fibroblasts. These findings demonstrate how cellular diversity across a transitional tissue may underlie microanatomical-specific roles. This atlas provides a foundation for understanding cellular functions across the tendon and adjoining muscle and will be essential for comparisons with diseased tissue, identifying pathogenic mediators and treatment targets for autoimmune and degenerative pathologies of the Achilles tendon. We present the first spatially resolved single-cell atlas of the human Achilles tendon. By sampling across the microanatomy of the tendon from enthesis to muscle, we demonstrate changes in fibroblast composition across this transitional tissue. Distinct fibroblast subsets were discovered with specific transcriptomic signatures, and several were found in distinct spatial locations corresponding to putative functional roles in tendon and adjoining muscle. These findings demonstrate how cellular diversity across a transitional tissue may underlie microanatomical-specific roles.
Harnessing AlphaFold3 to elucidate BBSome structure and protein partners.
Guo DF, Rouabhi Y, Tollefson M … +2 more , Vorhies K, Rahmouni K
Am J Physiol Cell Physiol · 2026 May · PMID 41915029 · Publisher ↗
The BBSome, an eight-protein complex implicated in Bardet-Biedl syndrome (BBS), plays a crucial role in various cellular processes including ciliary function. Although important aspects of its structural organization and...
The BBSome, an eight-protein complex implicated in Bardet-Biedl syndrome (BBS), plays a crucial role in various cellular processes including ciliary function. Although important aspects of its structural organization and protein interactions have been elucidated, additional questions remain regarding how these features relate to cargo recognition and complex dynamics. Using AlphaFold3, we generated a structural model closely matching recent cryo-EM data (α-carbon root means square deviation: 1.203 Å). Interface residue analysis of the model identified BBSome proteins BBS1 and BBS9 as central interaction hubs (most interface residues between two proteins), with BBS2 and BBS7 showing the most polar contacts. The common BBS1 pathogenic mutation, known to cause BBS, was predicted to destabilize the complex. BBS4 was also found to interact stably with pericentriolar material 1, suggesting a role in centriolar satellite localization. AlphaFold3-mediated analysis of BBSome interactions with G protein-coupled receptors (GPCRs) led to the identification of contact hotspots on BBS1, BBS4, and BBS5. These predictions were supported by immunoprecipitation and peptide competition assays. The modeling also suggested plausible interfaces between specific BBS proteins and metabolic signaling proteins, including melanocortin receptor accessory protein 2 (MRAP2) [an melanocortin-4 receptor (MC4R) chaperonin], the leptin receptor, and the insulin receptor. These predicted interfaces align with previously reported biochemical associations between BBS proteins and these receptors, supporting the idea that the BBSome regulates trafficking and signaling in metabolic pathways. Together, these findings provide new insights into BBSome structure and receptor interactions, offering a predictive framework to explore its role in ciliary trafficking and human disease. This study combines AI modeling and experimental validation to define key structural features and receptor interactions of the BBSome complex. The analysis identifies BBS1 and BBS9 as central hubs, reveals how the BBS1 mutation destabilizes the complex, and uncovers novel contacts with various receptors including those involved in metabolic regulation. These findings provide a predictive framework linking BBSome structure to ciliary signaling and metabolic regulation in Bardet-Biedl syndrome.
Forgotten foundations: basement membranes in lung function and cancer.
Yoo D, Cox TR, Parker AL
Am J Physiol Cell Physiol · 2026 Jun · PMID 41914976 · Publisher ↗
The basement membrane is a specialized extracellular matrix network that orchestrates fundamental cellular processes in many organs. In the lung, this dynamic scaffold provides compositionally encoded instructions that d...
The basement membrane is a specialized extracellular matrix network that orchestrates fundamental cellular processes in many organs. In the lung, this dynamic scaffold provides compositionally encoded instructions that direct epithelial differentiation, regulate injury responses, and modulate disease progression. Despite its fundamental importance, the basement membrane remains an understudied aspect of lung biology, with its precise composition, spatial organization, and biomechanical properties in health and disease poorly defined. This review synthesizes current understanding of lung epithelial basement membrane composition and function with emphasis on how this matrix layer supports lung development, injury repair, and cancer progression. We highlight evidence that basement membrane components are not merely structural supports but active regulators of cellular phenotype and discuss how this conceptual shift opens new therapeutic strategies in lung cancer.
Patched controls cell cycle and tissue architecture in gonad.
Farley JK, Schwalbe M, Forsberg F … +2 more , Amran A, Gopal S
Am J Physiol Cell Physiol · 2026 May · PMID 41914962 · Publisher ↗
Hedgehog (Hh) signaling is essential for embryonic development and tissue homeostasis in organisms. However lacks canonical Hh signaling due to the absence of key components, such as smoothened (SMO) and obvious Hh ligan...
Hedgehog (Hh) signaling is essential for embryonic development and tissue homeostasis in organisms. However lacks canonical Hh signaling due to the absence of key components, such as smoothened (SMO) and obvious Hh ligands. Despite this, retains Patched homologs, and , which have specialized independent functions. Although is predominantly expressed in the germline and in somatic tissues, we demonstrate that both genes are required to maintain germ cell populations and proper actin cytoskeletal architecture in the progenitor zone of the germline. Disruption of actin-encoding genes impairs germ cell S-phase and reduces the number of cells in the progenitor zone, indicating that cytoskeletal integrity is critical for maintaining the germline. Furthermore, defects observed upon loss of Patched function are linked to disruptions in cholesterol metabolism. We show that the phenotypes observed in the gonads due to dietary cholesterol changes can be modulated through Patched receptors. Together, our findings reveal a role for Patched receptors in regulating gonad architecture and germ cell development through cholesterol-sensitive functions, offering insights into how metabolic cues influence the organization of complex tissues. In this study, we demonstrate how two hedgehog signaling pathway receptors influence germ cell development and reproduction. We identified the roles of Patched receptors in regulating germ cell maintenance, a process that is likely dependent on cholesterol homeostasis. Our findings reveal that dietary cholesterol levels impact Patched-driven germ cell behavior and gonad structure, highlighting the critical role of Patched in germline development.
Titin immunoglobulin domain refolding produces mechanical work in situ.
Tiessen C, Leonard T, Herzog W
Am J Physiol Cell Physiol · 2026 May · PMID 41914915 · Publisher ↗
Titin's role in providing passive force in striated muscle is well-established. Generally, titin's elasticity is attributed to its unique PEVK region, a nearly elastic nonlinear spring. The remaining length of I-band tit...
Titin's role in providing passive force in striated muscle is well-established. Generally, titin's elasticity is attributed to its unique PEVK region, a nearly elastic nonlinear spring. The remaining length of I-band titin is largely composed of immunoglobulin (Ig) domains grouped into tandem-proximal and distal regions. Titin's Ig domains were long thought to unfold only under high forces and refold only under near-zero forces. Recent evidence from single-molecule Ig domain constructs indicates Ig domains may unfold and refold at physiological forces. We performed a series of passive stretch shortenings on intact rabbit psoas myofibrils to determine if Ig domain refolding may indeed occur during shortening to produce meaningful mechanical work in situ. We hypothesized refolding may occur quickly and under force, producing physiologically meaningful work. Using the established modified worm-like chain model for titin's PEVK, and a novel myofibril immunolabeling system providing, for the first time, simultaneous sarcomere force and PEVK length measurements, we approximated the mechanical work contribution of Ig domain refolding based on estimated I-band titin segmental lengths. In stretch-shortening protocols tested, we found Ig domain refolding contributes work during shortening, accounting for up to 25.6 ± 13.4% of energy recovered. We show Ig domain refolding occurs under forces of 5.6 ± 3.7 pN, within physiological ranges of forces experienced by titin filaments. Our findings in intact myofibrils, where full-length titin is in its in situ position, correspond closely to in vitro experiments using isolated titin fragments. We demonstrate Ig domain refolding is relevant to passive force and work production in situ, using isolated myofibrils. Titin's proximal immunoglobulin domains have been shown to unfold and refold at physiological forces in isolated protein constructs. In this study, we use mechanical testing of intact isolated rabbit psoas myofibrils coupled with mathematical modeling to confirm that immunoglobulin domain unfolding and refolding does indeed occur at physiological forces in situ. We show that immunoglobulin domains refold at physiological forces, when titin is situated in its physiological configuration in an intact sarcomere.
BAG3 modulates clathrin-mediated endocytosis and tau uptake in astrocytes.
Rodwell-Bullock J, Blau E, Ganguly A … +2 more , Deaton C, Johnson GVW
Am J Physiol Cell Physiol · 2026 May · PMID 41911062 · Full text
Astrocytes maintain neuronal homeostasis by removing extracellular disease-relevant proteins, such as tau, to prevent their uptake by neurons. In Alzheimer's disease (AD), this astrocytic function is impaired, contributi...
Astrocytes maintain neuronal homeostasis by removing extracellular disease-relevant proteins, such as tau, to prevent their uptake by neurons. In Alzheimer's disease (AD), this astrocytic function is impaired, contributing to pathological tau accumulation. Many AD-associated risk genes are linked to endocytosis pathways, suggesting their role in AD pathogenesis. Although astrocytes can internalize, degrade, and release tau, the mechanisms governing these processes remain unclear. Bcl2-associated athanogene 3 (BAG3), a multifunctional protein regulating vacuolar processes, interacts with components of clathrin-mediated endocytosis (CME), including clathrin heavy chain, dynamin, and AP-2 complex members. However, BAG3's role in astrocytic CME and tau processing is not fully understood. We demonstrate for the first time that BAG3 depletion in astrocytes reduces clathrin-AP-2 interactions, inhibits CME-dependent epidermal growth factor receptor internalization, and decreases tau uptake. Live cell imaging reveals impaired CME dynamics with BAG3 depletion, marked by prolonged clathrin particle lifetimes. BAG3 depletion also increases Lamp1+ puncta and colocalization of tau with Lamp1-positive structures, indicating vacuolar disturbances beyond CME. These findings suggest BAG3 facilitates CME, tau uptake, and trafficking in astrocytes, playing a critical role in vacuolar processes and tau proteostasis. Alterations in astrocytic BAG3 may contribute to AD pathogenesis and other proteinopathies. In this study, we demonstrate that the multifunctional protein BAG3 facilitates clathrin-mediated endocytosis (CME) and tau uptake in astrocytes. We show that BAG3 depletion reduces clathrin-AP-2 interactions, inhibits CME-dependent epidermal growth factor receptor internalization, and decreases tau uptake. BAG3 depletion impairs CME dynamics as indicated by prolonged clathrin particle lifetimes, and increases Lamp1+ puncta and colocalization of tau with Lamp1-positive structures, indicating vacuolar disturbances beyond CME.
Defocus coding and transcriptomic remodeling in the mouse myopic retina.
So C, Zhang T, Yang K … +3 more , Wang J, Yan-Yin Tse D, Pan F
Am J Physiol Cell Physiol · 2026 May · PMID 41910002 · Publisher ↗
The theory of visually guided ocular growth is well supported in explaining myopia, but how the retina senses focus versus defocus and converts the signaling into growth-modulating genetic signals remains unresolved. Usi...
The theory of visually guided ocular growth is well supported in explaining myopia, but how the retina senses focus versus defocus and converts the signaling into growth-modulating genetic signals remains unresolved. Using whole-cell recordings and single-cell RNA-seq in the mouse retina, we show that lateral inhibitory networks-horizontal cells in the outer retina, but not AII amacrine cells in the inner retina, respond to optical defocus. Dopaminergic amacrine cells (DACs) are maximally excited by focused images and increasingly inhibited by high blur, consistent with dopamine's anti-myopiagenic role. Single-cell RNA sequencing (scRNA-seq) revealed stable cell-class composition but coordinated, cell type-specific remodeling of gamma-aminobutyric acid (GABA)-ergic synapse and gap-junction pathways in lens-induced myopic (LIM) retinas. Consistent with a key role for retinal dopamine signaling, we found gene-level, cell-type-specific remodeling: and were significantly upregulated in highly myopic retinas, whereas multiple dopamine-pathway components (, , , , , , and ) were significantly downregulated. Together, our results support a general principle: neuromodulator-gated electrical coupling shapes computations for signal discrimination, and chronic sensory blur in LIM drives cross-level plasticity, from biophysical states to gene expression, that biases downstream coding and growth signals. Targeted manipulation of dopaminergic signaling may restore adaptive defocus encoding and slow myopic progression. Using lens-induced myopia as a model of blurred vision, we show that retinal circuits adapt to defocus in a cell type-specific way. Horizontal cell network, but not AII amacrine cell networks, alter their responses, whereas dopaminergic amacrine cells undergo early biophysical changes followed by transcriptional remodeling of the dopamine pathway. This cross-level adaptation, from synapses to gene expression, supports robust vision under uncertainty and suggests dopaminergic signaling as a target to restore healthy defocus encoding.
Neuronal growth regulator 1 modulates actin dynamics to control intracellular GLUT4 trafficking.
Yun SY, Lee S
Am J Physiol Cell Physiol · 2026 May · PMID 41902694 · Publisher ↗
NEGR1 (neuronal growth regulator 1) has been genetically linked to metabolic and neuropsychiatric disorders; however, its cellular function in insulin-responsive tissues remains poorly understood. Here, we investigated t...
NEGR1 (neuronal growth regulator 1) has been genetically linked to metabolic and neuropsychiatric disorders; however, its cellular function in insulin-responsive tissues remains poorly understood. Here, we investigated the role of NEGR1 in regulating actin cytoskeletal dynamics and insulin-stimulated GLUT4 trafficking in skeletal muscle. We found that loss of reduced GLUT4 abundance selectively in predominantly glycolytic skeletal muscles in vivo. Despite preserved insulin-induced Akt phosphorylation, insulin-stimulated GLUT4 translocation was markedly impaired in both Negr1-deficient and NEGR1-overexpressing muscle cells. Mechanistically, deficiency was associated with enhanced PAK-cofilin signaling and excessive intracellular F-actin accumulation that likely impedes GLUT4 vesicle trafficking. In contrast, NEGR1 overexpression did not increase total F-actin content but induced abnormal peripheral actin organization, resulting in constitutive GLUT4 surface localization and elevated basal glucose uptake. Consistent with these findings, both loss and overexpression of NEGR1 disrupted insulin-induced Rac1-dependent actin remodeling without affecting Akt signaling. Collectively, these results identify NEGR1 as a critical modulator of actin homeostasis required for proper insulin-stimulated GLUT4 trafficking and glucose uptake in skeletal muscle, providing mechanistic insight into the metabolic abnormalities associated with NEGR1 dysregulation. Neuronal growth regulator 1 (NEGR1) regulates actin cytoskeletal homeostasis required for insulin-stimulated GLUT4 trafficking in skeletal muscle. NEGR1 dysregulation alters PAK-cofilin signaling, induces aberrant F-actin organization, and impairs GLUT4 vesicle movement independent of Akt signaling. Because NEGR1 is a major genetic risk factor for major depressive disorder, these findings reveal a shared actin-based mechanism linking metabolic dysfunction and neuropsychiatric disease.
Cellular senescence in skeletal muscle: myogenic and nonmyogenic cell populations, mechanisms, and therapeutic opportunities.
Papanikolaou K, Yadav A, Mankowski RT … +5 more , Alexander MS, Gamboa JL, Thalacker-Mercer AE, Dungan CM, Englund DA
Am J Physiol Cell Physiol · 2026 May · PMID 41886266 · Publisher ↗
Skeletal muscle plays a central role in systemic metabolism, physical function, and overall health. Aging and disease diminish the ability of myogenic and nonmyogenic skeletal muscle cells to coordinate adaptation and re...
Skeletal muscle plays a central role in systemic metabolism, physical function, and overall health. Aging and disease diminish the ability of myogenic and nonmyogenic skeletal muscle cells to coordinate adaptation and repair, but the mechanisms underlying this decline are not fully understood. Growing evidence implicates cellular senescence, a stress response marked by irreversible cell cycle arrest and proinflammatory signaling, as a key contributor to muscle pathology. In this review, we synthesize current insights into the molecular mechanisms that govern cellular senescence in skeletal muscle, its effects on myogenic and nonmyogenic cell populations, and recent technologies that have clarified key aspects of senescence biology. We further explore emerging therapeutic strategies aimed at targeting senescent cells and discuss key knowledge gaps that must be addressed to advance our understanding of senescent myogenic and nonmyogenic cells in skeletal muscle.
BDNF alters β-cleavage of APP and subcellular distribution of BACE1.
Hallam RD, Foran G, Fletcher NK … +2 more , MacPherson REK, Necakov A
Am J Physiol Cell Physiol · 2026 May · PMID 41871009 · Publisher ↗
The accumulation and deposition of amyloid-beta (Aβ) peptides is detrimental to neuronal networks and is driven by the cleavage of amyloid precursor protein (APP) by beta-secretase 1 (BACE1). The proteolytic processing o...
The accumulation and deposition of amyloid-beta (Aβ) peptides is detrimental to neuronal networks and is driven by the cleavage of amyloid precursor protein (APP) by beta-secretase 1 (BACE1). The proteolytic processing of APP is tightly regulated by the opposing activities of BACE1 and ADAM10, with the latter producing a truncated, nonamyloidogenic fragment. Maintaining this balance is critical for normal physiological function, as complete inhibition of BACE1 has proven detrimental owing to the important physiological roles of its many substrates. Brain-derived neurotrophic factor (BDNF), an important mediator of neuronal function and survival, has recently been shown to reduce BACE1 activity in neural tissue, but the mechanism for this remains unknown. Previous research suggests that BACE1 cleavage of APP is favored at acidic intracellular compartments, whereas nonamyloidogenic processing preferentially occurs at the plasma membrane. Hence, we hypothesized that BDNF alters the subcellular distribution of BACE1, reducing β-cleavage of APP. Here, we show that acute BDNF treatment of differentiated neural cells (SH-SY5Y) reduced levels of sAPPβ, a product of BACE1 cleavage of APP. Using confocal microscopy and quantitative image analysis, we found that this reduction in sAPPβ levels is coincident with increased BACE1 localization to the plasma membrane and a concomitant reduction of BACE1 localization to early endosomes. This effect appears to be independent of clathrin-mediated endocytosis (CME), as inhibition of CME by PitStop2 treatment increased α-cleavage of APP but did not reduce β-cleavage independent of BDNF treatment. Hence, BDNF may reduce the production of Aβ by altering BACE1 distribution and decreasing upstream β-cleavage. BACE1 cleavage of APP generates amyloid-β, overproduction of which perturbs physiological function in the brain. The neurotrophic factor BDNF reduces BACE1 cleavage of APP, potentially reducing amyloid-β production in the brain. Here, we show that this may be the result of BDNF altering the subcellular distribution of BACE1, reducing localization to acidic compartments where enzymatic activity is increased. This effect is independent of clathrin-mediated endocytosis, as BACE1 cleavage of APP is unchanged by PitStop2 treatment.
Enhanced hypoxia resistance distinguishes human pluripotent stem cell-derived islets from primary islets.
Kato H, Shang KM, Mitsugashira H … +7 more , Qi M, Suzuki T, Stock PG, Toyoda T, Tai YC, Kandeel F, Komatsu H
Am J Physiol Cell Physiol · 2026 May · PMID 41870990 · Full text
Hypoxia during the early posttransplant period represents a major barrier to successful cellular transplantation. This limitation is particularly relevant for pancreatic islet transplantation, a clinical treatment option...
Hypoxia during the early posttransplant period represents a major barrier to successful cellular transplantation. This limitation is particularly relevant for pancreatic islet transplantation, a clinical treatment option for diabetes. Stem cell-derived islets are an emerging potential alternative to current primary islets obtained from deceased donors. Although stem cell-derived cells are generally assumed to be more hypoxia-tolerant than primary cells, direct quantitative evidence supporting this assumption has been limited, particularly in comparisons between stem cell-derived islets and primary islets. Here, we applied a recently developed Po__survivalmetric to objectively compare hypoxia resistance between human primary adult islets and human-induced pluripotent stem cell-derived islet spheroids. Using controlled hypoxic culture, live/dead imaging, and computational oxygen modeling, we quantified the Po_survival as a local oxygen tension at the boundary between viable and nonviable regions within three-dimensional islet constructs. Po_survival of stem cell-derived islets was significantly lower than that of primary islets (0.01 mmHg vs. 2.24 mmHg; < 0.0001), quantitatively demonstrating enhanced hypoxia resistance of stem cell-derived islet cells. Computational analyses integrating intraspheroidal oxygen distributions and hypoxia resistance further demonstrated improved estimated survival of stem cell-derived islets under large spheroid and hypoxic conditions. Together, these findings provide quantitative evidence that stem cell-derived islets possess enhanced hypoxia resistance compared with primary human islets. This property may expand feasible transplantation sites and reduce early graft loss in stem cell-derived islet therapies. This study provides the first quantitative evidence that human stem cell-derived islets are more resistant to hypoxia than primary human islets. Stem cell-derived islets maintain viability at substantially lower oxygen levels and exhibit markedly reduced variability in hypoxia tolerance. These findings identify hypoxia resistance as a key functional advantage of stem cell-derived islets, with important implications for transplantation into low-oxygen environments and for scalable islet fabrication strategies.
CTLA4-Ig reduces proliferation and inflammatory gene expression in muscle fibroblasts, corresponding to less fibrosis and inflammation in muscular dystrophy.
Wehling-Henricks M, Kannan P, Thomas C … +5 more , Bal H, Balu V, Ochi E, Dorshkind K, Tidball JG
Am J Physiol Cell Physiol · 2026 May · PMID 41855092 · Publisher ↗
Muscle pathology in Duchenne muscular dystrophy (DMD) is greatly amplified by the immune response to dystrophic muscle, which provides the rationale for targeting the immune system in DMD therapies. Much of immune-driven...
Muscle pathology in Duchenne muscular dystrophy (DMD) is greatly amplified by the immune response to dystrophic muscle, which provides the rationale for targeting the immune system in DMD therapies. Much of immune-driven pathology in the mouse model of DMD is caused by T-lymphocytes and macrophages; thus, preventing T-cell activation by blocking pathways that cause their activation has the potential to reduce muscle damage and fibrosis in muscular dystrophy. CTLA4-Ig is a recombinant protein that blocks costimulatory signaling between T-cells and antigen-presenting cells, such as macrophages. In this investigation, we tested whether treatment of mice until they reach advanced, fibrotic stages of the disease reduces pathology. Our findings show that CTLA4-Ig treatments reduced muscle damage and inflammation and also reduced numbers of fibrogenic cells and fibrosis of muscles in aging, mice. However, the treatments did not reduce numbers of CD8+ T-cells or activated CD25+ cells, suggesting that the reduced pathology was not mediated by affecting T-cell activation. Complete blood counts and clinical histopathological scoring also showed that the treatments had little effect on hematopoietic tissues. In vitro, CTLA4-Ig acted directly on muscle fibroblasts, reducing their expression of proinflammatory genes without affecting the expression of genes encoding connective tissue proteins, assayed by quantitative PCR (qPCR). However, CTLA4-Ig-treated fibroblasts were less proliferative in vitro. Collectively, these findings show that CTLA4-Ig acts directly on fibroblasts to produce changes in proliferation and gene expression that are consistent with the reductions in muscle pathology that occurs in aging, mice treated with CTLA4-Ig. This investigation shows that CTLA4-Ig, which blocks costimulatory signaling between immune cells, is effective at reducing fibrosis and inflammation in aging, dystrophic muscle. CTLA4-Ig acts directly on muscle fibroblasts, causing reductions in their proliferation and expression of proinflammatory genes.
SK channels as antiarrhythmic targets for atrial fibrillation: structural and pharmacological perspectives.
McKie MK, Meibom EH, Ramirez AG … +2 more , Soattin L, Bentzen BH
Am J Physiol Cell Physiol · 2026 Jun · PMID 41849797 · Publisher ↗
Small-conductance Ca-activated K (SK) channels have emerged as promising atrial-selective targets for rhythm control in atrial fibrillation (AF). Genetic association studies, functional experiments, and early clinical tr...
Small-conductance Ca-activated K (SK) channels have emerged as promising atrial-selective targets for rhythm control in atrial fibrillation (AF). Genetic association studies, functional experiments, and early clinical trials collectively support a role for SK channels in atrial repolarization and AF maintenance. Recent breakthroughs in single-particle cryo-electron microscopy have provided high-resolution structures of the SK2 channel, revealing unique architectural features that underlie its low conductance and susceptibility to pharmacological modulation. Numerous studies have shown alterations in SK transcript abundance in AF in both humans and animal models. However, recent functional studies have demonstrated dynamic regulation of SK channel gating and membrane trafficking in AF, highlighting context-dependent pro- and antiarrhythmic effects. This mini review summarizes the recent structural and functional advances in our understanding of SK channels and emerging therapeutic implications for AF.
A long-term human adipocyte organoid model reveals aging-associated responses to intermittent hypoxia.
Dong Y, Wang J, Feng F … +5 more , Ali IH, Chen L, Karim S, Bock JM, Somers VK
Am J Physiol Cell Physiol · 2026 Apr · PMID 41849272 · Publisher ↗
Obstructive sleep apnea (OSA), characterized by recurrent intermittent hypoxia (IH), is increasingly recognized as a driver of adipose tissue dysfunction, insulin resistance, and accelerated aging. However, current in vi...
Obstructive sleep apnea (OSA), characterized by recurrent intermittent hypoxia (IH), is increasingly recognized as a driver of adipose tissue dysfunction, insulin resistance, and accelerated aging. However, current in vitro models inadequately recapitulate the long-term effects of IH on human adipocytes. Here, we developed a robust long-term human adipocyte organoid culture system that models IH-induced adipocyte aging in vitro. Human stromal vascular fraction cells isolated from subcutaneous abdominal adipose tissue were embedded in Matrigel and seeded into Biofloat U-bottom 96-well plates. Using a 1:1 Matrigel-cell mixture and optimized seeding volumes (5-20 µL), adipocyte organoids formed within 10-12 days and maintained stable morphology and viability for more than 90 days. Matrigel was essential for structural integrity, whereas gelatin and low-melting agarose failed to support organoid formation. Subcutaneous preadipocyte medium supplemented with 10% FBS supported more robust adipogenic differentiation and long-term maintenance than advanced/F12K medium. To model OSA-associated hypoxic stress, organoids were exposed to programmable IH. IH suppressed adipogenesis, as evidenced by reduced lipid accumulation, downregulation of adipogenic markers (PPARγ, adiponectin, and FABP4), and reduced lipid droplets. Transmission electron microscopy revealed IH-induced ultrastructural abnormalities, including endoplasmic reticulum fragmentation, mitochondrial disruption, nuclear enlargement, and heterochromatin accumulation-features consistent with cellular senescence. IH further upregulated hypoxia-inducible factor 1α, H2AX, repressive histone methylation marks (H3K9me3, H3K79me3, and H4K20me3), and extracellular matrix remodeling proteins (fibronectin and lysyl oxidase), while impairing insulin signaling as demonstrated by reduced PI3K and AKT phosphorylation. Collectively, these findings establish a physiologically relevant human adipocyte organoid platform for investigating IH-induced adipocyte dysfunction and aging. Establishes a robust long-term human adipocyte organoid culture system maintained for over 90 days. Recapitulates key features of OSA-related intermittent hypoxia in human adipocytes in vitro. Demonstrates IH-induced adipocyte aging, including ultrastructural damage and epigenetic reprogramming. Identifies impaired adipogenesis and insulin signaling under intermittent hypoxia. Provides a physiologically relevant platform for mechanistic studies and drug screening.
The cellular basis of fibrotic tendon healing: now in higher definition.
Chafouleas ZJ, Ackerman JE, Loiselle AE … +1 more , Nichols AEC
Am J Physiol Cell Physiol · 2026 Apr · PMID 41843903 · Full text
Tendon injuries are common and heal through the formation of a fibrotic scar rather than regeneration. This poor natural healing results in impaired function and increases the risk of reinjury. In 2019, we reviewed the c...
Tendon injuries are common and heal through the formation of a fibrotic scar rather than regeneration. This poor natural healing results in impaired function and increases the risk of reinjury. In 2019, we reviewed the current state of the field's understanding of the cellular basis of fibrotic tendon healing, focusing on the resident and infiltrating cell populations that appear at key stages and what was known about their role in tendon healing at the time. Since then, advances in transcriptomic technologies and widespread adoption of lineage tracing have refined our understanding of these processes. This updated review reexamines the key cellular players in tendon healing and summarizes new studies into their origins, dynamics, and potential interactions during healing. Specifically, we highlight recent insights into peripheral compartmental complexity, fibroblast heterogeneity, the emerging role of the adaptive immune system, and potential cellular cross talk in both tendon homeostasis and healing. We also discuss potential therapeutic targets aimed at modulating cell behavior to reduce fibrosis while promoting tendon regeneration and highlight new gaps in knowledge that are critical for continued progress in the field. This review serves as an updated guide to understanding the cellular drivers of fibrotic tendon healing and for informing the development of new therapeutic strategies to improve tendon healing outcomes.
Cerebral capillary computation.
Longden TA
Am J Physiol Cell Physiol · 2026 May · PMID 41843902 · Full text
This article synthesizes recent evidence to propose a framework for control of energy delivery in the brain in which the capillary bed functions as an active, distributed signal-processing network that senses neuronal ac...
This article synthesizes recent evidence to propose a framework for control of energy delivery in the brain in which the capillary bed functions as an active, distributed signal-processing network that senses neuronal activity and metabolic state and converts these inputs into electrical commands that regulate upstream diameter to control blood flow. Capillary endothelial cells (ECs) form an electrically coupled syncytium via gap junctions, whereas pericytes are vertically integrated into this network at peg-socket junctions, enabling bidirectional electrical communication. It is proposed that thin-strand pericytes and their associated underlying ECs constitute a "capillary computational unit" (CCU): a local transformer-like module in which pericytes act as rich multimodal sensors and signal generators, whereas ECs are optimized for signal amplification and long-range transmission. Emphasis is placed on the ion channel toolkit that implements CCU computations, with discussion of how different conductances shape membrane voltage to encode local energetic demand and propagate signals over long distances. Kir2.1 channels emerge as a keystone conductor and regenerative carrier of hyperpolarizing signals; K channels couple energy status and adenosine levels/glucose availability with electrical output; small- and intermediate-conductance Ca-activated K channels in the arteriole-capillary transition zone provide amplification; transient receptor potential and Piezo1 channels impose depolarizing and mechanosensory feedback constraints; and chloride channels (notably TMEM16A) act as voltage tethers that clamp or reset local membrane potential. Framing these elements computationally suggests that addition and subtraction, gain control, shunting, and veto-like logic may arise naturally from network architecture and channel biophysics.
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