Biology subjects

Lemoff, A.

Publications and source records attributed to Lemoff, A..

17 recordsLinked to original sources

bioRxiv2026

Glutathione Protects Hematopoietic Stem Cells from Proteotoxic Stress

Glutathione is a redox buffer, best known for preventing oxidative stress and ferroptosis, but rarely studied in stem cells. We studied glutathione function in hematopoietic stem cells (HSCs) by deleting the glutamate-cysteine ligase catalytic subunit (GCLC), which synthesizes glutathione, or glutathione peroxidase 4 (GPX4), which employs glutathione to prevent ferroptosis. GCLC deficiency eliminated glutathione from hematopoietic cells, severely impairing HSC function and hematopoiesis. In contrast, GPX4 deficiency did not affect HSC function and had little effect on hematopoiesis, even after vitamin E depletion, suggesting glutathione has ferroptosis-independent functions in HSCs. Consistent with this, GCLC deficiency increased reactive oxygen species levels in hematopoietic cells. But treatment with antioxidants or ferroptosis inhibitors gave little or no rescue of HSC function despite reducing ROS levels. Rather, GCLC-deficient, but not GPX4-deficient, HSCs exhibited unfolded protein accumulation, proteostatic stress, and cell death marked by elevated p53 levels and Annexin V staining. Deficiency for p53 prolonged the function of GCLC-deficient HSCs after transplantation. Glutathione is thus necessary in HSCs for proteostasis but may be dispensable for ferroptosis inhibition in vivo.

cell biology↗

bioRxiv2026

Mitochondrial perturbation adapts the proteome from early to advanced immune responses

Dysregulated immunity, a hallmark of many human diseases, co-occurs with mitochondrial dysfunction and is commonly associated with misprimed primary immune signaling. While transcriptionally well-characterized, the impact of mitochondria on the host response at the protein level is less clear. Using in vitro and in vivo approaches including proteotranscriptomics, our data suggest that OXPHOS promotes expression of early, cell autonomous immune proteins whereas mitochondrial perturbation favors mediators of cell extrinsic responses like inflammation. This response is independent of immune cues, time-dependent, conserved, and occurs across tissues in mouse models of mitochondrial dysfunction. These data illustrate unappreciated roles for mitochondrial state in adapting host responses at the protein level, which have implications for complex disease etiology and the ancestral origins for eukaryotic immune sensing.

immunology↗

bioRxiv2026

A tissue-resolved endothelial surface proteome atlas informs organ-selective vascular targeting

BACKGROUND Endothelial cells (ECs) exhibit organ-specific functional diversity that shapes vascular homeostasis, disease susceptibility, and therapeutic accessibility. Although single-cell transcriptomic studies have defined endothelial heterogeneity at the RNA level, the in vivo cell-surface protein landscape that directly mediates vascular signaling and drug targeting remains incompletely characterized. Here, we mapped organ-specific endothelial surface proteomes atlas in vivo to define tissue-enriched vascular protein candidates relevant to organ-selective therapeutic design. METHODS We generated Cdh5-CreERT; Cre-iPEEL mice, referred to here as CHRP mice, in which membrane-tethered horseradish peroxidase is induced selectively in ECs after tamoxifen treatment, and compared CHRP labeling with non-selective NHS-Biotin vascular labeling. Following in vivo biotin-phenol perfusion, endothelial surface proteins were enriched by streptavidin affinity purification and analyzed by mass spectrometry across six organs. Proteomic profiles were used to resolve tissue- and subtype-associated endothelial surface signatures, compare protein and transcript detection patterns, and nominate tissue-selective endothelial membrane candidates, which were annotated using ChEMBL compound-target information. RESULTS Compared with non-selective NHS-Biotin labeling, CHRP improved endothelial specificity and produced clearer separation of tissue-resolved endothelial surface proteomes across brain, white adipose tissue, small intestine, kidney, lung, and skeletal muscle. CHRP proteomics revealed pronounced organ-specific heterogeneity and resolved canonical arterial, venous, and capillary programs, as well as specialized endothelial signatures including blood-brain barrier and glomerular endothelial features. Comparison with single-cell endothelial references revealed systematic differences between transcriptomic and proteomic detection of endothelial membrane proteins. Further analysis identified tissue-selective endothelial membrane candidates, and ChEMBL annotation linked a subset of these candidates to existing compound-target records, supporting the candidate atlas as a resource for future tissue-selective vascular targeting studies. CONCLUSIONS CHRP-based in vivo proximity labeling enables systematic, protein-level mapping of organ-specific endothelial surface proteomes. Together with transcriptomic comparison and compound-target annotation, this study provides a tissue-resolved endothelial surfaceome resource for vascular biology and future organ-selective therapeutic target evaluation.

cell biology↗

bioRxiv2026

ApoE4 Promotes Thrombosis via Endothelial Cell ApoER2 and PP2A Activation

Background: APOE4, the variant of apolipoprotein E carried by 25% of individuals, is a common genetic risk factor for cardiovascular disease (CVD). Although ApoE classically participates in lipid transport, APOE4-associated risk goes beyond impact on circulating lipids. Life-threatening CVD events including myocardial infarction and stroke are driven by atherogenesis and thrombosis. In mice ApoE4 increases atherosclerosis severity, but whether other major drivers of CVD events are influenced by ApoE4 is unknown. Methods: GWAS data for venous thromboembolism (VTE) were analyzed. In humanized APOE3 (hE3) and APOE4 (hE4) mice, thrombosis was assessed by intravital microscopy (IVM) in the mesenteric microcirculation and by inferior vena cava (IVC) partial ligation. Actions of ApoE3 versus ApoE4 on endothelial cells (EC) and their underpinnings were studied in cultured human and mouse aortic EC, interrogating interactomes with immunoprecipitation-mass spectrometry and quantifying the secretion of Von Willebrand Factor (vWF), a critical initiator of thrombosis. Single cell transcriptomics datasets were queried do localize endothelial cell gene expression. Results: GWAS showed that APOE4 is associated with increased VTE risk, and whereas plasma lipids were similar, both microvascular and venous thrombosis were markedly increased in hE4 compared to hE3 mice. In cultured EC, whereas ApoE3 attenuated vWF secretion, it was enhanced by ApoE4, and both processes were mediated by ApoE receptor 2 (ApoER2). ApoE4, but not ApoE3, suppressed VEGF eNOS activation and NO production by causing the recruitment of the protein phosphatase 2A (PP2A) catalytic subunit to ApoER2 and the activation of PP2A. PP2A deletion prevented ApoE4-induced eNOS antagonism and vWF secretion by preserving Akt activation, and the NO donor spermine NONOate negated apoE4 stimulation of vWF secretion. PP2A activity was increased in hE4 aortas and IVC, and EC ApoER2 deletion or pharmacologic PP2A inhibition fully prevented exaggerated thrombosis in hE4 mice. In human great saphenous vein ApoER2 is primarily expressed in valvular endothelium. Conclusions: APOE4 is a risk allele for thrombosis, and ApoE4 is prothrombotic in microvasculature and veins in mice. Mechanistically, the ApoE4-EC ApoER2 tandem enhances vWF secretion by recruiting and activating PP2A and antagonizing eNOS, resulting in exaggerated thrombosis. In human veins ApoER2 is expressed in valvular endothelium, which is the most common site of initiation of venous thrombosis. Targeting these processes may afford protection from both primary thrombotic disorders like VTE and acute CVD events such as myocardial infarction and stroke in 25% of the population.

pathology↗

bioRxiv2026

Hyperosmolar stress promotes the release of small extracellular vesicles containing metabolic proteins from corneal epithelial cells

PurposeHyperosmolar stress (HOS) is a major contributor to corneal epithelial cell damage in dry eye disease. We have previously shown that HOS damages mitochondria and impairs cell metabolism in corneal epithelial cells. Small extracellular vesicles (sEVs) are cell-derived lipid envelopes that are present in all body fluids, including tears. Prior studies suggest that sEV release and composition may be linked with changes in cell metabolism. In this study, we tested the effects of HOS on sEV release and composition, and found that sEV cargo may reflect early, underlying changes in dry eye disease. MethodsTelomerase-immortalized human corneal epithelial (hTCEpi) cells were treated with 450 mOsm NaCl for five days to induce chronic HOS. sEVs were isolated using differential centrifugation followed by iodixanol density gradient flotation. Particle number was determined using Nanoparticle Tracking Analysis (NTA). Mass spectrometry was used to assess the sEV proteome, and selected proteins were validated by immunoblot. Proteome pathways were analyzed using KEGG and CORUM. ResultsPathway analysis revealed an increase in metabolic proteins and proteasome components in sEV cargo released from hTCEpi cells exposed to HOS. These proteins were increased more than fourfold in HOS-sEVs. Examination of proteins involved in the endosomal pathway and NTA further confirmed an increase in HOS-sEV release. ConclusionOur findings suggest a potential mechanism whereby corneal epithelial cells exposed to HOS retain proteins involved in maintaining tissue integrity, while simultaneously releasing unneeded proteins involved in cell metabolism. The presence of metabolic proteins in sEVs may serve as early indicators of dry eye disease.

cell biology↗

bioRxiv2025

Role of tankyrase scaffolding in the β-catenin destruction complex and WNT signaling

Aberrant WNT/{beta}-catenin signaling drives tumorigenesis and metastasis in cancer. Although enzymatic inhibitors of tankyrase (TNKS) effectively block AXIN degradation and stabilize the {beta}-catenin destruction complex (DC), they have demonstrated limited efficacy in various cancer models. Here we demonstrate that, unexpectedly, the induction of AXIN puncta represents a major barrier to achieving therapeutic efficacy. Mechanistically, catalytic inhibition of TNKS prevents TNKS turnover and drives its accumulation in the DC, wherein the scaffolding function of TNKS induces AXIN puncta formation, rigidifies the DC, and impedes {beta}-catenin turnover. Chemically induced degradation of TNKS overcomes this limitation by stabilizing AXIN without puncta formation, providing a deeper suppression of the WNT/{beta}-catenin pathway activity and the proliferation of colorectal cancer cells harboring dysfunctional APC mutations. Collectively, these findings provide an explanation for the unsatisfactory outcomes of drugging the WNT/{beta}-catenin signaling pathway by TNKS inhibitors and highlight TNKS degradation as a promising approach to treat WNT/{beta}-catenin-driven cancers.

cancer biology↗

bioRxiv2025

Translational control of innate barrier defense by the gut microbiota

The intestinal epithelium is protected by a mucus barrier, infused with antimicrobial proteins, that restricts microbial access to host tissue. Because assembling this barrier is energetically costly, its production must be tightly regulated. Here, we show that the microbiota regulates the translation of key mucus barrier components, including the structural glycoprotein mucin 2 and the antimicrobial enzyme lysozyme. This process is initiated by microbial induction of histone deacetylase 5 (HDAC5) in secretory epithelial cells of the intestine. HDAC5 promotes deacetylation of 14-3-3 proteins, enabling activation of the energy sensing kinase mTOR which enhances translation of mucus and antimicrobial proteins. These findings reveal a mechanism by which the microbiota controls barrier immunity at the level of protein synthesis and suggest that the HDAC5-mTOR axis integrates microbial and energetic signals to regulate intestinal defense. One sentence summaryThe gut microbiota enhances translation of innate barrier defense proteins through HDAC5-mediated activation of mTORC1 signaling.

immunology↗

bioRxiv2025

A Shared Amyloid Architecture in Cardiac Fibrils from Three Neuropathy-Associated ATTR Variants

ATTR amyloidosis results from the systemic accumulation of wild-type (ATTRwt) or mutant (ATTRv) transthyretin amyloids, leading to multi-organ dysfunction and death. The disease exhibits variable pathology and penetrance, and its relationship with the amyloid structure remains unclear. Patients carrying the neuropathy-associated variants ATTRvI84S and ATTRv-V122{Delta} present polymorphic ATTR fibrils, in contrast to the consistent morphology reported for most ATTR fibrils to date. Here, we aim to elucidate a potential link between neuropathic symptomatology, distinct mutations, and amyloid structural diversity, using cryo-EM. We determined the ex-vivo fibril structures from the variants ATTRv-P24S, ATTRv-A25S, and ATTRv-D38A, whose patients presented variable clinical manifestations, including neuropathy. Our findings revealed that, despite differences in mutations and diverse clinical phenotypes, these variants share a common amyloid core previously identified in ATTRwt and several other cardiac ATTRv. This structural consistency is significant for the development of structure-guided diagnostic tools capable of addressing the diverse spectrum of ATTR amyloidosis. HighlightsO_LIDetermines transthyretin amyloid structures of three human ATTRv by cryo-EM C_LIO_LIDetermines the structure of three ex-vivo ATTRv fibrils linked to polyneuropathy. C_LIO_LIReveals structural similarities of ATTRv amyloid cores. C_LIO_LIReveals a common fold despite the different mutations and symptomatology. C_LIO_LIContributes to the understanding of transthyretin aggregation in patients with diverse phenotypes C_LI

biophysics↗

bioRxiv2025

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice

Conventional stable isotope tracing assays track one or several metabolites. However, cells use an array of nutrients to sustain nitrogen metabolic pathways. This incongruency hampers a system level understanding of cellular nitrogen metabolism. Therefore, we created a platform to simultaneously trace 30 nitrogen isotope-labeled metabolites. This platform revealed that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine despite expressing de novo pathway enzymes. This link between cell state and pyrimidine synthesis routes persisted in physiological contexts, including primary murine and human tissues and tumor xenografts. Mechanistically, we found that Ser1900 phosphorylation of CAD, the first enzyme of the de novo pathway, was enriched in primitive cells and that mimicking this modification in differentiated cells abrogated their preference for pyrimidine salvage. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.

cell biology↗

bioRxiv2025

Structural polymorphism of ex-vivo ALECT2 amyloid fibrils revealed by cryo-EM

ALECT2 amyloidosis is a rare systemic disease characterized by the pathological deposition of leukocyte cell-derived chemotaxin-2 (LECT2) as amyloid fibrils, primarily affecting the kidneys and liver. The molecular mechanisms underlying LECT2 aggregation remain poorly defined, hindering diagnostic and therapeutic development. Here, we present cryo-electron microscopy structures of ex-vivo ALECT2 fibrils extracted from a patients kidney. We identified three fibril polymorphs: a predominant single-protofilament morphology and two minor double-protofilament morphologies. The dominant single-protofilament morphology comprises the full-length 133-residue LECT2 protein and retains all three native disulfide bonds. Low-resolution reconstructions of double-protofilament morphologies suggest they adopt a similar fold to the single protofilament morphology, but form paired assemblies with different inter-filament interfaces. Mass spectrometry also reveals acetylation within the fibrils. These findings offer critical insights into the structural basis of ALECT2 amyloid formation and identify molecular features that could inform future diagnostic and therapeutic approaches.

biophysics↗

bioRxiv2025

Structural variability of apolipoprotein A-I amyloid fibrils across organs, mutations, and clinical presentations, revealed by cryo-EM

Hereditary apolipoprotein A-I (AapoA-I) amyloidosis is a rare systemic disease caused by the deposition of amyloid fibrils formed by apolipoprotein A-I in multiple organs, leading to severe clinical outcomes. With no available therapies or diagnostic tools, defining the structure of AApoA-I fibrils is crucial to understanding disease mechanisms and guiding intervention. Using cryo-electron microscopy, we analyzed AApoA-I fibrils from the heart, kidney, liver, and spleen of patients carrying G26R, L90P, and R173P mutations. G26R fibrils, regardless of organ, exhibited untwisted morphologies and could not be resolved structurally. Conversely, L90P and R173P fibrils displayed a compact diabolo-shaped conformation in all organs analyzed. Their high-resolution maps enabled visualization of cis-Proline 66, which may represent a potential conformational switch during fibril formation. Our findings suggest that mutation-driven polymorphism may influence organ tropism and clinical presentation. This work advances our understanding of AapoA-I fibril assembly and provides insights toward developing targeted clinical tools.

biophysics↗

bioRxiv2024

ATTRv-V30M Type A amyloid fibrils from the heart and nerves exhibit structural homogeneity.

ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.

biophysics↗

bioRxiv2024

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found an unprecedented structural variability in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically-different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structures impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies. One-Sentence Summary: Wild-type cardiac ATTR fibrils are structurally homogeneous.

biophysics↗

bioRxiv2023

VCP increases or decreases tau seeding using specific cofactors

BackgroundNeurodegenerative tauopathies may progress based on seeding by pathological tau assemblies, whereby an aggregate is released from one cell, gains entry to an adjacent or connected cell, and serves as a specific template for its own replication in the cytoplasm. In vitro seeding reactions typically take days, yet seeding into the complex cytoplasmic milieu can happen within hours. A cellular machinery might regulate this process, but potential players are unknown. MethodsWe used proximity labeling to identify factors that control seed amplification. We fused split-APEX2 to the C-terminus of tau repeat domain (RD) to reconstitute peroxidase activity upon seeded intracellular tau aggregation. We identified valosin containing protein (VCP/p97) 5h after seeding. Mutations in VCP underlie two neurodegenerative diseases, multisystem proteinopathy and vacuolar tauopathy, but its mechanistic role is unclear. We utilized tau biosensors, a cellular model for tau aggregation, to study the effects of VCP on tau seeding. ResultsVCP knockdown reduced tau seeding. However, distinct chemical inhibitors of VCP and the proteasome had opposing effects on aggregation, but only when given <8h of seed exposure. ML-240 increased seeding efficiency [~]40x, whereas NMS-873 decreased seeding efficiency by 50%, and MG132 increased seeding [~]10x. We screened VCP co-factors in HEK293 biosensor cells by genetic knockout or knockdown. Reduction of ATXN3, NSFL1C, UBE4B, NGLY1, and OTUB1 decreased tau seeding, as did NPLOC4, which also uniquely increased soluble tau levels. Reduction of FAF2 and UBXN6 increased tau seeding. ConclusionsVCP uses distinct cofactors to determine seed replication efficiency, consistent with a dedicated cytoplasmic processing complex that directs seeds towards dissolution vs. amplification.

cell biology↗

bioRxiv2023

Iron acquisition by a commensal bacterium modifies host nutritional immunity during Salmonella infection

During intestinal inflammation, host nutritional immunity starves microbes of essential micronutrients such as iron. Pathogens scavenge iron using siderophores, which is counteracted by the host using lipocalin-2, a protein that sequesters iron-laden siderophores, including enterobactin. Although the host and pathogens compete for iron in the presence of gut commensal bacteria, the roles of commensals in nutritional immunity involving iron remain unexplored. Here, we report that the gut commensal Bacteroides thetaiotaomicron acquires iron in the inflamed gut by utilizing siderophores produced by other bacteria including Salmonella, via a secreted siderophore-binding lipoprotein termed XusB. Notably, XusB-bound siderophores are less accessible to host sequestration by lipocalin-2 but can be "re-acquired" by Salmonella, allowing the pathogen to evade nutritional immunity. As the host and pathogen have been the focus of studies of nutritional immunity, this work adds commensal iron metabolism as a previously unrecognized mechanism modulating the interactions between pathogen and host nutritional immunity.

microbiology↗

bioRxiv2022

Insulin receptor substrate 4 deficiency mediates the insulin effect on the epithelial magnesium channel TRPM6 and causes hypomagnesemia

The kidney is the key regulator of magnesium (Mg2+) homeostasis in the human body. In the distal convoluted tubule (DCT), the apical epithelial magnesium (Mg2+) channel TRPM6, determines how much Mg2+ is excreted in the urine. To better understand the regulation of human renal Mg2+ absorption we identified novel, potential interaction partners of TRPM6 by pursuing a liquid chromatography - tandem mass spectrometry (LC-MS/MS) proteomics approach. We found insulin receptor substrate 4 (IRS4) enriched with TRPM6 tagged to glutathione S-transferase (TRPM6-GST) but not GST control. Physical interaction between IRS4 and TRPM6 was confirmed by co-immunoprecipitation. Applying microdissection of mouse tubules, we detected Irs4 mRNA expression mostly in the DCT and to a lower degree in the proximal tubule and thick ascending limb of Henle. Given the overall low abundance of Irs4 mRNA along the tubule we investigated the phenotype of Irs4 knockout mice (Irs4-/-). These Irs4-/- mice displayed significantly higher urinary and fecal Mg2+ losses and lower blood Mg2+ levels than wild-type (WT) mice. Claudin-16, claudin-19, and Hnf1b mRNA and Claudin-16 and Trpm6 protein expression was significantly higher in kidneys of 3 month old Irs4-/- mice consistent with a compensatory mechanism to conserve Mg2+. Applying whole-cell patch-clamp recording we confirmed the stimulatory role of insulin on TRPM6 channel activity and showed that IRS4 targets the two TRPM6 phosphorylation sites T1391 and S1583 to enhance TRPM6 current density. To test the effect of Mg2+ deficiency on metabolism, we performed glucose and insulin tolerance studies, which were mildly abnormal in Irs4-/- mice. SIGNIFICANCE STATEMENTMagnesium (Mg2+) is the second most abundant intracellular cation but the regulation of Mg2+ homeostasis is not well understood. The kidney is the key organ for regulating Mg2+ homeostasis. Insulin is a known stimulator of the apical epithelial Mg2+channel TRPM6. We present a novel modifier of Mg2+ absorption with insulin receptor substrate 4 (IRS4) which illuminates further, how insulin activates the TRPM6 channel and modifies Mg2+ homeostasis. Applying protein biochemistry, tubular microdissection, whole mouse physiology, and patch-clamp recording, we demonstrate that IRS4 mediates the stimulatory effect of insulin by enhancing phosphorylation of two specific TRPM6 residues. Irs4-/- mice develop increased urinary and stool Mg2+ losses, lower serum Mg2+ concentration, and display mild impairment in glucose and insulin tolerance.

physiology↗

bioRxiv2021

Angiocrine IGFBP3 Spatially Coordinates IGF Signaling During Neonatal Cardiac Regeneration

To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating neonatal hearts for differentially-expressed secreted proteins - which we hypothesized could include candidate mitogens. We identified and validated IGFBP3, which has a Janus-like stabilizing and sequestering effect on IGF growth factors, as a neonatal injury-associated secreted protein. IGFBP3 is expressed by and secreted from vascular cells in the neonatal heart after cardiac injury, notably in the infarct border zone. We found that global deletion of IGFBP3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 and a transgenic mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the adult heart. We show that site-specific expression of an IGFBP3 protease (PAPP-A2) and its inhibitor (STC2) coordinate the spatial release of IGF2 in the infarct zone to regio-selectively activate the INSR-ERK-AKT cell growth pathways in cardiomyocytes. Collectively, our work highlights the spatiotemporal orchestration of endothelial-cardiomyocyte interactions that are required for neonatal cardiac regeneration.

cell biology↗