Organ-specific Functions Research Articles

Growth hormone signaling and clinical implications: from molecular to therapeutic perspectives.

Growth hormone (GH) is a key polypeptide hormone secreted by somatotroph cells in the anterior pituitary gland, essential for postnatal growth, metabolism, and systemic homeostasis. Its secretion is regulated by hypothalamic neuropeptides, including GH-releasing hormone and somatostatin. GH exerts effects through direct interaction with the growth hormone receptor and indirect pathways mediated by the GH-IGF-I axis. GHR activation triggers signaling pathways, such as JAK-STAT, PI3K/AKT, and MAPK, promoting cellular proliferation, differentiation, and metabolic balance. The GH-IGF-I axis is critical for bone growth, lipid and carbohydrate metabolism, and organ-specific physiological functions. Dysregulation of GH results in diverse disorders. Congenital deficiencies, like isolated GH deficiency and syndromic conditions (e.g., Turner syndrome), stem from genetic mutations. Acquired deficiencies arise from trauma, tumors, infections, or autoimmune damage, while GH overproduction causes gigantism in children and acromegaly in adults, often due to pituitary adenomas. Idiopathic deficiencies, lacking identifiable causes, complicate management further. Advances in therapy have transformed outcomes for GH disorders. Recombinant human growth hormone provides effective replacement therapy for deficiencies. Somatostatin analogs, dopamine receptor agonists, and GH receptor antagonists are pivotal for managing GH excess. Surgical and radiotherapeutic interventions remain essential for pituitary adenomas. However, GH therapy requires close monitoring to prevent side effects like insulin resistance and metabolic complications. This review provides a comprehensive evaluation of the molecular mechanisms underlying GH action, its physiological roles, GH-related disorders, and therapeutic approaches to optimize patient outcomes.

Microenvironmental determinants of endothelial cell heterogeneity.

During development, endothelial cells (ECs) undergo an extraordinary specialization by which generic capillary microcirculatory networks spanning from arteries to veins transform into patterned organotypic zonated blood vessels. These capillary ECs become specialized to support the cellular and metabolic demands of each specific organ, including supplying tissue-specific angiocrine factors that orchestrate organ development, maintenance of organ-specific functions and regeneration of injured adult organs. Here, we illustrate the mechanisms by which microenvironmental signals emanating from non-vascular niche cells induce generic ECs to acquire specific inter-organ and intra-organ functional attributes. We describe how perivascular, parenchymal and immune cells dictate vascular heterogeneity and capillary zonation, and how this system is maintained through tissue-specificsignalling activatedbyvasculogenic and angiogenic factors and deposition of matrix components. We also discuss how perturbation of organotypic vascular niche cues lead to erasure of EC signatures,contributing to the pathogenesis of disease processes. We alsodescribe approaches that use reconstitution of tissue-specific signatures of ECs to promote regeneration of damaged organs.

Adenosine diphosphate stimulates VEGF-independent choroidal endothelial cell proliferation: A potential escape from anti-VEGF therapy

We hypothesized that a strategy employing tissue-specific endothelial cells (EC) might facilitate the identification of tissue- or organ-specific vascular functions of ubiquitous metabolites. An unbiased approach was employed to identify water-soluble small molecules with mitogenic activity on choroidal EC. We identified adenosine diphosphate (ADP) as a candidate, following biochemical purification from mouse EL4 lymphoma extracts. ADP stimulated the growth of bovine choroidal EC (BCEC) and other bovine or human eye-derived EC. ADP induced rapid phosphorylation of extracellular signal-regulated kinase in a dose- and time-dependent manner. ADP-induced BCEC proliferation could be blocked by pretreatment with specific antagonists of the purinergic receptor P2Y1 but not with a vascular endothelial growth factor (VEGF) inhibitor, indicating that the EC mitogenic effects of ADP are not mediated by stimulation of the VEGF pathway. Intravitreal administration of ADP expanded the neovascular area in a mouse model of choroidal neovascularization. Single-cell transcriptomics from human choroidal datasets show the expression of P2RY1, but not other ADP receptors, in EC with a pattern similar to VEGFR2. Although ADP has been reported to be a growth inhibitor for vascular EC, here we describe its growth-stimulating effects for BCEC and other eye-derived EC.

Epigenetic regulation of organ-specific functions in Mikania micrantha and Mikania cordata: insights from DNA methylation and siRNA integration

BackgroundDNA methylation is a crucial epigenetic mechanism that regulates gene expression during plant growth and development. However, the role of DNA methylation in regulating the organ-specific functions of the invasive weed Mikania micrantha remains unknown.ResultsHere, we generated DNA methylation profiles for M. micrantha and a local congeneric species, Mikania cordata, in three vegetative organs (root, stem, and leaf) using whole-genome bisulfite sequencing. The results showed both differences and conservation in methylation levels and patterns between the two species. Combined with transcriptome data, we found that DNA methylation generally inhibited gene expression, with varying effects depending on the genomic region and sequence context (CG, CHG, and CHH). Genes overlapping with differentially methylated regions (DMRs) were more likely to be differentially expressed between organs, and DMR-associated upregulated differentially expressed genes (DEGs) were enriched in organ-specific pathways. A comparison between photosynthetic (leaf) and non-photosynthetic (root) organs of M. micrantha further confirmed the regulatory role of DNA methylation in leaf-specific photosynthesis. Integrating small RNA-Seq data revealed that 24-nt small interfering RNAs (siRNAs) were associated with CHH methylation in gene-rich regions and regulated CHH methylation in the flanking regions of photosynthesis-related genes.ConclusionThis study provides insights into the complex regulatory role of DNA methylation and siRNAs in organ-specific functions and offers valuable information for exploring the invasive characteristics of M. micrantha from an epigenetic perspective.

Advanced technologies for the study of neuronal cross-organ regulation: a narrative review

The nervous system plays an integral role in the homeostasis of living organisms through the regulation of multiple organ systems. Research has highlighted the extensive role of the nervous system in regulating organ function, including key aspects such as metabolic processes, respiratory, cardiovascular, and immune responses. These findings are inseparable from the development of new technologies such as viral tracing, optogenetics, whole-tissue imaging, and neural activity recording. As technology continues to advance, our understanding of the regulatory role of the nervous system in other organs has expanded to more complex cognitive and emotional control systems, such as the cerebral cortex and subcortical areas. Recent studies have also shown the bidirectional cross-organ regulatory mechanisms between the gut microbiota and the brain. In addition, the body–brain axis also monitors inflammatory responses to ensure a balance between proinflammatory and anti-inflammatory responses. This review delves into the intricate regulatory functions of the nervous system as they pertain to cross-organ communication, emphasizing the broader implications that extend beyond mere metabolic regulation. It employs cutting-edge technologies such as viral tracing, whole-tissue clearing, optogenetics, and in vivo neuronal activity recording to dissect the influence of the nervous system on various organs, including but not limited to the heart, liver, and spleen. These advanced methodologies have substantially broadened our comprehension of the fundamental operations of the nervous system within diverse physiological systems, revealing the complex neural networks that orchestrate organ-specific functions. Our review highlights the significant potential of advanced technologies in neuronal cross-organ regulation to pave the way for therapeutic strategies aimed at addressing a wide array of conditions that impact organ health.

Recent advances in brain organoids: a comprehensive review of the last eight years

Organoids are three-dimensional cellular structures grown in vitro that can self-organize and differentiate into cell types with organ-specific functions, closely mimicking the biological properties of tissues and organs in vivo. Brain organoids, which differentiate into structures resembling brain function, serve as valuable models for medical research, including disease microenvironment simulation, brain mechanism exploration, and drug evaluation. In this review, we analyzed 808 articles retrieved from PubMed, CNKI, and Wanfang databases using the keyword "brain organoids," of which 180 were included. We summarized the research progress of brain organoids over the past eight years by categorizing and refining the findings. Our analysis shows that brain organoids have achieved significant success in simulating brain development in vitro, leading to the establishment and refinement of 3D brain organoid models for disease research. Brain organoids have been widely applied to explore disease-related mechanisms, yielding promising results and opening avenues for further research on the human brain. In this review, we summarize the progress of brain organoids in three areas: culture methods, disease-related research, and brain exploration.

Organoids: development and applications in disease models, drug discovery, precision medicine, and regenerative medicine.

Organoids are miniature, highly accurate representations of organs that capture the structure and unique functions of specific organs. Although the field of organoids has experienced exponential growth, driven by advances in artificial intelligence, gene editing, and bioinstrumentation, a comprehensive and accurate overview of organoid applications remains necessary. This review offers a detailed exploration of the historical origins and characteristics of various organoid types, their applications-including disease modeling, drug toxicity and efficacy assessments, precision medicine, and regenerative medicine-as well as the current challenges and future directions of organoid research. Organoids have proven instrumental in elucidating genetic cell fate in hereditary diseases, infectious diseases, metabolic disorders, and malignancies, as well as in the study of processes such as embryonic development, molecular mechanisms, and host-microbe interactions. Furthermore, the integration of organoid technology with artificial intelligence and microfluidics has significantly advanced large-scale, rapid, and cost-effective drug toxicity and efficacy assessments, thereby propelling progress in precision medicine. Finally, with the advent of high-performance materials, three-dimensional printing technology, and gene editing, organoids are also gaining prominence in the field of regenerative medicine. Our insights and predictions aim to provide valuable guidance to current researchers and to support the continued advancement of this rapidly developing field.

The use of stem cells in the treatment of diabetes mellitus and its complications - review

Introduction and purpose Diabetes is a disease resulting from impaired action or secretion of insulin. The number of patients currently amounts to approximately 422 million, and approximately 1.5 million deaths per year are directly attributed to this disease. Diabetes significantly reduces the quality of life and, if poorly controlled, can lead to serious complications. Mesenchymal stem cells are multipotent cells capable of differentiation. They have the ability to self-renew and have a modulating function. There are reports that they can be used in the treatment of this disease. The aim of the review was to present a new method of therapy and their possible effects. Material and methods The review was based on articles obtained from PubMed scientific database in the years 2015-2023, using the following keywords: diabetes mellitus, stem cells, diabetes complications. Results Implanted stem cells are able to transform into cells that produce and secrete insulin, and also enable better glycemic control. They can alleviate chronic inflammation and reduce fibrosis. Taking into account the complications that occur during long-term diabetes, the use of stem cells may be associated with improving the function of specific organs and tissues such as the kidneys, heart, eyes and nerves. Studies also report a positive effect of these cells on the healing process of wounds and ulcers. Conclusions Stem cells are a promising object of analysis. They can control glycemia and have a positive effect on the functioning of the kidneys, heart, eyes and nerves, and accelerate wound healing, but further, extensive research is needed to assess the effectiveness and safety of this therapy.

Tiny Organs, Big Impact: How Microfluidic Organ-on-Chip Technology Is Revolutionizing Mucosal Tissues and Vasculature.

Organ-on-chip (OOC) technology has gained importance for biomedical studies and drug development. This technology involves microfluidic devices that mimic the structure and function of specific human organs or tissues. OOCs are a promising alternative to traditional cell-based models and animals, as they provide a more representative experimental model of human physiology. By creating a microenvironment that closely resembles in vivo conditions, OOC platforms enable the study of intricate interactions between different cells as well as a better understanding of the underlying mechanisms pertaining to diseases. OOCs can be integrated with other technologies, such as sensors and imaging systems to monitor real-time responses and gather extensive data on tissue behavior. Despite these advances, OOCs for many organs are in their initial stages of development, with several challenges yet to be overcome. These include improving the complexity and maturity of these cellular models, enhancing their reproducibility, standardization, and scaling them up for high-throughput uses. Nonetheless, OOCs hold great promise in advancing biomedical research, drug discovery, and personalized medicine, benefiting human health and well-being. Here, we review several recent OOCs that attempt to overcome some of these challenges. These OOCs with unique applications can be engineered to model organ systems such as the stomach, cornea, blood vessels, and mouth, allowing for analyses and investigations under more realistic conditions. With this, these models can lead to the discovery of potential therapeutic interventions. In this review, we express the significance of the relationship between mucosal tissues and vasculature in organ-on-chip (OOC) systems. This interconnection mirrors the intricate physiological interactions observed in the human body, making it crucial for achieving accurate and meaningful representations of biological processes within OOC models. Vasculature delivers essential nutrients and oxygen to mucosal tissues, ensuring their proper function and survival. This exchange is critical for maintaining the health and integrity of mucosal barriers. This review will discuss the OOCs used to represent the mucosal architecture and vasculature, and it can encourage us to think of ways in which the integration of both can better mimic the complexities of biological systems and gain deeper insights into various physiological and pathological processes. This will help to facilitate the development of more accurate predictive models, which are invaluable for advancing our understanding of disease mechanisms and developing novel therapeutic interventions.

Multi-organ single-cell transcriptomics of immune cells uncovered organ-specific gene expression and functions

Despite the wealth of publicly available single-cell datasets, our understanding of distinct resident immune cells and their unique features in diverse human organs remains limited. To address this, we compiled a meta-analysis dataset of 114,275 CD45+ immune cells sourced from 14 organs in healthy donors. While the transcriptome of immune cells remains relatively consistent across organs, our analysis has unveiled organ-specific gene expression differences (GTPX3 in kidney, DNTT and ACVR2B in thymus). These alterations are linked to different transcriptional factor activities and pathways including metabolism. TNF-α signaling through the NFkB pathway was found in several organs and immune compartments. The presence of distinct expression profiles for NFkB family genes and their target genes, including cytokines, underscores their pivotal role in cell positioning. Taken together, immune cells serve a dual role: safeguarding the organs and dynamically adjusting to the intricacies of the host organ environment, thereby actively contributing to its functionality and overall homeostasis.

Enhancing subcellular protein localization mapping analysis using Sc2promap utilizing attention mechanisms

BackgroundAberrant protein localization is a prominent feature in many human diseases and can have detrimental effects on the function of specific tissues and organs. High-throughput technologies, which continue to advance with iterations of automated equipment and the development of bioinformatics, enable the acquisition of large-scale data that are more pattern-rich, allowing for the use of a wider range of methods to extract useful patterns and knowledge from them. MethodsThe proposed sc2promap (Spatial and Channel for SubCellular Protein Localization Mapping) model, designed to proficiently extract meaningful features from a vast repository of single-channel grayscale protein images for the purposes of protein localization analysis and clustering. Sc2promap incorporates a prediction head component enriched with supplementary protein annotations, along with the integration of a spatial-channel attention mechanism within the encoder to enables the generation of high-resolution protein localization maps that encapsulate the fundamental characteristics of cells, including elemental cellular localizations such as nuclear and non-nuclear domains. ResultsQualitative and quantitative comparisons were conducted across internal and external clustering evaluation metrics, as well as various facets of the clustering results. The study also explored different components of the model. The research outcomes conclusively indicate that, in comparison to previous methods, Sc2promap exhibits superior performance. ConclusionsThe amalgamation of the attention mechanism and prediction head components has led the model to excel in protein localization clustering and analysis tasks. General significanceThe model effectively enhances the capability to extract features and knowledge from protein fluorescence images.

Thyroid Hormone Biomonitoring: A Review on Their Metabolism and Machine-Learning Based Analysis on Effects of Endocrine Disrupting Chemicals.

The thyroid is an essential endocrine organ in human body, and thyroid hormones (THs) are pivotal signaling molecules and mediators in various physiological processes. THs, particularly in their free form, play a critical role in regulating body temperature and in the metabolism of lipid and glucose, making the maintenance of TH levels crucial for human health. THs undergo a series of metabolic processes, producing TH metabolites (THMs). THMs are significant in endocrine regulation, such as 3,5-diiothyronine (3,5-T2) and 3-iodothyronamine (3-T1AM), which exhibit activities akin to THs. The production and distribution of THMs are intricately linked to the function of specific organs and tissues, highlighting the need for advanced research into the determination and mechanisms of THMs in body. Exposure to endocrine disrupting chemicals (EDCs) can significantly affect the levels of thyroid stimulating hormone (TSH) and THs. This review utilizes machine learning to analyze epidemiological data, identifying potential EDCs that pose risks of hyperthyroidism and hypothyroidism. Additionally, it delves into the toxicological mechanisms of these EDCs, examining their effects on TH production, binding processes, related proteins, and metabolic enzymes. This approach effectively bridges the gap between epidemiological studies and toxicological researches, laying the groundwork for future research trends. By integrating epidemiological studies with machine learning, this review offers insightful perspectives on the potential risks associated with chemical exposure and underscores the necessity for further research in understanding the impact of EDCs on TH metabolism and TH-related health effects.

Effects of tree size and organ age on variations in carbon, nitrogen, and phosphorus stoichiometry in Pinus koraiensis

Carbon (C), nitrogen (N), and phosphorus (P) are of fundamental importance for growth and nutrient dynamics within plant organs and deserve more attention at regional to global scales. However, our knowledge of how these nutrients vary with tree size, organ age, or root order at the individual level remains limited. We determined C, N, and P contents and their stoichiometric ratios (i.e., nutrient traits) in needles, branches, and fine roots at different organ ages (0–3-year-old needles and branches) and root orders (1st–4th order roots) from 64 Pinus koraiensis of varying size (Diameter at breast height ranged from 0.3 to 100 cm) in northeast China. Soil factors were also measured. The results show that nutrient traits were regulated by tree size, organ age, or root order rather than soil factors. At a whole-plant level, nutrient traits decreased in needles and fine roots but increased in branches with tree size. At the organ level, age or root order had a negative effect on C, N, and P and a positive effect on stoichiometric ratios. Our results demonstrate that nutrient variations are closely related to organ-specific functions and ecophysiological processes at an individual level. It is suggested that the nutrient acquisition strategy by younger trees and organ fractions with higher nutrient content is for survival. Conversely, nutrient storage strategy in older trees and organ fractions are mainly for steady growth. Our results clarified the nutrient utilization strategies during tree and organ ontogeny and suggest that tree size and organ age or root order should be simultaneously considered to understand the complexities of nutrient variations.

Human organ chips for regenerative pharmacology.

Human organs-on-chips (organ chips) are small microfluidic devices that allow human cells to perform complex organ-level functions invitro by recreating multi-cellular and multi-tissue structures and applying invivo-like biomechanical cues. Human Organ Chips are being used for drug discovery and toxicology testing as an alternative to animal models which are ethically challenging and often do not predict clinical efficacy or toxicity. In this mini-review, we summarize our presentation that reviewed the state of the art relating to these microfluidic culture devices designed to mimic specific human organ structures and functions, and the application of Organ Chips to regenerative pharmacology.

CCBE1 regulates the development and prevents the age-dependent regression of meningeal lymphatics

Recent studies have described the importance of lymphatics in numerous organ-specific physiological and pathological processes. The role of meningeal lymphatics in various neurological and cerebrovascular diseases has been suggested. It has also been shown that these structures develop postnatally and are altered by aging and that the vascular endothelial growth factor C (VEGFC)/ vascular endothelial growth factor receptor 3 (VEGFR3) signaling plays an essential role in the development and maintenance of them. However, the molecular mechanisms governing the development and maintenance of meningeal lymphatics are still poorly characterized. Recent in vitro cell culture-based experiments, and in vivo studies in zebrafish and mouse skin suggest that collagen and calcium binding EGF domains 1 (CCBE1) is involved in the processing of VEGFC. However, the organ-specific role of CCBE1 in developmental lymphangiogenesis and maintenance of lymphatics remains unclear. Here, we aimed to investigate the organ-specific functions of CCBE1 in developmental lymphangiogenesis and maintenance of meningeal lymphatics during aging. We demonstrate that inducible deletion of CCBE1 leads to impaired postnatal development of the meningeal lymphatics and decreased macromolecule drainage to deep cervical lymph nodes. The structural integrity and density of meningeal lymphatics are gradually altered during aging. Furthermore, the meningeal lymphatic structures in adults showed regression after inducible CCBE1 deletion. Collectively, our results indicate the importance of CCBE1-dependent mechanisms not only in the development, but also in the prevention of the age-related regression of meningeal lymphatics. Therefore, targeting CCBE1 may be a good therapeutic strategy to prevent age-related degeneration of meningeal lymphatics.

Single-Cell Transcriptomic Analysis of Dental Pulp and Periodontal Ligament Stem Cells

The regeneration of periodontal, periapical, and pulpal tissues is a complex process requiring the direct involvement of cells derived from pluripotent stem cells in the periodontal ligament and dental pulp. Dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) are spatially distinct with the potential to differentiate into similar functional and phenotypic cells. We aimed to identify the cell heterogeneity of DPSCs and PDLSCs and explore the differentiation potentials of their specialized organ-specific functions using single-cell transcriptomic analysis. Our results revealed 7 distinct clusters, with cluster 3 showing the highest potential for differentiation. Clusters 0 to 2 displayed features similar to fibroblasts. The trajectory route of the cell state transition from cluster 3 to clusters 0, 1, and 2 indicated the distinct nature of cell differentiation. PDLSCs had a higher proportion of cells (78.6%) at the G1 phase, while DPSCs had a higher proportion of cells at the S and G2/M phases (36.1%), mirroring the lower cell proliferation capacity of PDLSCs than DPSCs. Our study suggested the heterogeneity of stemness across PDLSCs and DPSCs, the similarities of these 2 stem cell compartments to be potentially integrated for regenerative strategies, and the distinct features between them potentially particularized for organ-specific functions of the dental pulp and periodontal ligament for a targeted regenerative dental tissue repair and other regeneration therapies.

Anti-Inflammatory Effects of Peripheral Dopamine.

Dopamine is synthesized in the nervous system where it acts as a neurotransmitter. Dopamine is also synthesized in a number of peripheral organs as well as in several types of cells and has organ-specific functions and, as demonstrated more recently, is involved in the regulation of the immune response and inflammatory reaction. In particular, the renal dopaminergic system is very important in the regulation of sodium transport and blood pressure and is particularly sensitive to stimuli that cause oxidative stress and inflammation. This review is focused on how dopamine is synthesized in organs and tissues and the mechanisms by which dopamine and its receptors exert their effects on the inflammatory response.

Organ-specific off-target effects of Pim/ZIP kinase inhibitors suggest lack of contractile Pim kinase activity in prostate, bladder, and vascular smooth muscle.

Smooth muscle contraction by Pim kinases and ZIPK has been suggested, but evidence for lower urinary tract organs or using Pim-selective inhibitor concentrations is not yet available. Here, we assessed effects of the Pim inhibitors AZD1208 and TCS PIM-1 and the dual ZIPK/Pim inhibitor HS38 on contractions of human prostate and bladder tissues and of porcine interlobar arteries. Human tissues were obtained from radical prostatectomy and radical cystectomy and renal interlobar arteries from pigs. Contractions were studied in an organ bath. Noradrenaline-, phenylephrine- and methoxamine-induced contractions were reduced (up to > 50%) with 500-nM AZD1208 in prostate tissues and to lesser degree and not consistently with all agonists in interlobar arteries. A total of 100-nM AZD1208 or 500-nM TCS PIM-1 did not affect agonist-induced contractions in prostate tissues. Decreases in agonist-induced contractions with 3-µM HS38 in prostate tissues and interlobar arteries were of small extent and did not occur with each agonist. Carbachol-induced contractions in detrusor tissues were unchanged with AZD1208 (500nM) or HS38. Electric field stimulation-induced contractions were not affected with AZD1208 or HS38 in any tissue, but slightly reduced with 500-nM TCS PIM-1 in prostate tissues. Concentration-dependent effects of Pim inhibitors suggest lacking Pim-driven smooth muscle contraction in the prostate, bladder, and interlobar arteries but point to organ-specific functions of off-targets. Procontractile functions of ZIPK in the prostate and interlobar arteries may be limited and are lacking in the detrusor.

Organoids as complex (bio)systems.

Organoids are three-dimensional structures derived from stem cells that mimic the organization and function of specific organs, making them valuable tools for studying complex systems in biology. This paper explores the application of complex systems theory to understand and characterize organoids as exemplars of intricate biological systems. By identifying and analyzing common design principles observed across diverse natural, technological, and social complex systems, we can gain insights into the underlying mechanisms governing organoid behavior and function. This review outlines general design principles found in complex systems and demonstrates how these principles manifest within organoids. By acknowledging organoids as representations of complex systems, we can illuminate our understanding of their normal physiological behavior and gain valuable insights into the alterations that can lead to disease. Therefore, incorporating complex systems theory into the study of organoids may foster novel perspectives in biology and pave the way for new avenues of research and therapeutic interventions to improve human health and wellbeing.

Peptide-Functionalized Electrospun Meshes for the Physiological Cultivation of Pulmonary Alveolar Capillary Barrier Models in a 3D-Printed Micro-Bioreactor.

In vitro environments that realize biomimetic scaffolds, cellular composition, physiological shear, and strain are integral to developing tissue models of organ-specific functions. In this study, an in vitro pulmonary alveolar capillary barrier model is developed that closely mimics physiological functions by combining a synthetic biofunctionalized nanofibrous membrane system with a novel three-dimensional (3D)-printed bioreactor. The fiber meshes are fabricated from a mixture of polycaprolactone (PCL), 6-armed star-shaped isocyanate-terminated poly(ethylene glycol) (sPEG-NCO), and Arg-Gly-Asp (RGD) peptides by a one-step electrospinning process that offers full control over the fiber surface chemistry. The tunable meshes are mounted within the bioreactor where they support the co-cultivation of pulmonary epithelial (NCI-H441) and endothelial (HPMEC) cell monolayers at air-liquid interface under controlled stimulation by fluid shear stress and cyclic distention. This stimulation, which closely mimics blood circulation and breathing motion, is observed to impact alveolar endothelial cytoskeleton arrangement and improve epithelial tight junction formation as well as surfactant protein B production compared to static models. The results highlight the potential of PCL-sPEG-NCO:RGD nanofibrous scaffolds in combination with a 3D-printed bioreactor system as a platform to reconstruct and enhance in vitro models to bear a close resemblance to in vivo tissues.