The central insight of the review is that autoimmune pathology emerges within spatially organized inflammatory niches rather than from isolated molecular defects. In systemic sclerosis, early microvascular destabilization driven by oxidative stress and anti-endothelial autoantibodies triggers endothelial apoptosis and endothelial-to-mesenchymal transition. Fibroblasts then undergo metabolic and epigenetic reprogramming, marked by persistent activation of the mechanotransductive regulators YAP/TAZ and MRTF-A, which keeps collagen production running even after soluble inflammatory cues fade. This creates what the authors call mechanical memory: extracellular matrix accumulates, tissue stiffens, and the stiffening itself amplifies fibroblast activation in a self-reinforcing loop that consolidates fibrosis in skin and lung.

Systemic lupus erythematosus follows a different but equally structured trajectory. Nucleic acid-containing immune complexes deposit along vascular and epithelial interfaces, where they activate plasmacytoid dendritic cells, neutrophils, and stromal cells through Fcγ receptors and the innate nucleic acid sensors TLR7 and TLR9. The result is robust type I interferon production, which conditions epithelial and endothelial layers to become fragile, reducing their mitochondrial reserve and increasing sensitivity to complement attack and mechanical stress. Spatial transcriptomics of patient tissue reveals persistent interferon hubs where interferon-stimulated genes remain highly expressed and tight junction maintenance is impaired. NET-associated oxidized mitochondrial DNA further activates the cGAS–STING pathway, intensifying interferon signaling and vascular dysfunction in a feed-forward cascade.

Rheumatoid arthritis, meanwhile, centers on cytokine-saturated stromal invasion. Autoantibodies against citrullinated antigens activate macrophages and neutrophils, flooding the synovium with TNF, IL-1β, IL-6, and GM-CSF. Within this niche, fibroblast-like synoviocytes rewire their metabolism toward glycolysis, activate AP-1/NF-κB enhancer programs, and resist apoptosis, differentiating into invasive subsets. Lining-layer synoviocytes secrete MMP and ADAMTS proteases that degrade cartilage, while sublining populations recruit immune cells through CXCL12 and GM-CSF. The stromal programs also drive RANKL-dependent osteoclastogenesis, linking inflammation directly to bone destruction. Each disease, in other words, selectively amplifies shared microenvironmental circuits—matrix remodeling, barrier destabilization, and self-sustaining cytokine loops—into a distinct pathogenic axis.

The review’s key contribution is translating these axes into engineering specifications. For systemic sclerosis, models must incorporate dynamically stiffening matrices, endothelial compartments capable of undergoing endothelial-to-mesenchymal transition under shear stress, and oxygen- and pressure-responsive microenvironments. Photoresponsive or enzyme-remodeled hydrogels allow researchers to interrogate mechanical memory acquisition directly, while perfusable microvascular chips reproduce shear-dependent endothelial activation under controlled oxygen tension and reactive oxygen species exposure. Existing iPSC-derived skin organoids exposed to TGF-β, IL-6, or patient serum already reproduce collagen accumulation, α-SMA induction, and SMAD and ERK signaling, preserving donor-specific fibroblast epigenetic states that reflect individual profibrotic sensitivity.

For lupus, the engineering requirements center on flow-dependent immune-complex deposition and interferon-responsive barrier tissues. Intestinal organoids exposed to lupus serum exhibit robust type I interferon activation, tight-junction disruption, reduced goblet-cell differentiation, and falling transepithelial electrical resistance. Kidney organoids and glomerular chips model immune-complex deposition, complement-mediated podocyte injury, and endothelial activation, while cardiac spheroids exposed to anti-Ro autoantibodies reproduce fibrosis, hypertrophy, and disrupted calcium signaling. Because lupus behaves as a multi-organ interferonopathy, the authors argue that multicompartment perfusion platforms are needed to recreate interferon gradients, cytokine spillover, and immune-complex trafficking across gut, kidney, heart, and vascular interfaces—something no single-organ model can achieve.

Rheumatoid arthritis platforms take a different form. Synovial organoids composed of patient-derived fibroblast-like synoviocytes, macrophages, and endothelial cells self-organize into persistent TNF/IL-6/GM-CSF niches that stabilize invasive stromal phenotypes and pathological angiogenesis—features absent from two-dimensional cultures. Joint-on-a-chip systems go further, spatially coupling synovium-like tissue with cartilage and bone matrices under flow and cyclic mechanical loading, enabling real-time observation of protease-mediated cartilage erosion and osteoclast-driven bone resorption as integrated mechanisms of joint destruction. Multicellular spheroids stimulated with synovial fluid or VEGF produce pannus-like outgrowth and macrophage-dependent inflammatory amplification, extending the framework toward drug screening.

Personalization is where the platform concept becomes clinically ambitious. Patient-derived induced pluripotent stem cells retain donor-specific transcriptional and epigenetic features, including genetic risk variants. CRISPR editing allows direct interrogation of disease genes: introducing lupus-risk variants such as DNASE1L3, IRF5, STAT4, and TLR7 enhances interferon responsiveness, while correcting pathogenic alleles restores barrier integrity. Editing HLA-DRB1 shared-epitope sequences or PTPN22 variants in rheumatoid arthritis organoids modulates T-cell help and Th17 polarization. A third layer comes from serum-based personalization, in which exposure to patient sera enriched for specific autoantibodies—ACPA, anti-Ro, anti-RNP, or anti-PDGFR—produces donor-specific fibrosis, interferon activation, or matrix degradation. Iteratively tuning organoid conditions until transcriptomic and structural profiles converge with biopsy signatures could yield what the authors call organoid digital twins capable of patient-specific therapeutic testing.

The engineering toolkit underpinning these models is itself a major theme. Synthetic PEG-based hydrogels with tunable crosslinking kinetics allow stiffness to be matched quantitatively to diseased tissue ranges, from sub-kilopascal basement-membrane-like matrices for lupus barrier fragility to tens-of-kilopascal collagen networks for scleroderma dermis. Viscoelastic properties such as stress relaxation shape integrin clustering, cytoskeletal tension, and nuclear deformation, while protease-cleavable linkers permit real-time quantification of matrix degradation. Spatial patterning techniques—micropatterned co-cultures, photo-patterned hydrogels, chemokine-laden matrices—position immune cells relative to stromal compartments, recreating perivascular interferon hubs, fibrotic immune aggregates, and invasive pannus fronts. Analytical tools including atomic force microscopy, second-harmonic generation imaging, single-cell RNA sequencing, spatial transcriptomics, and matrisome proteomics convert fibrosis, barrier failure, and immune infiltration into measurable engineering parameters.

The authors are candid about the limitations. iPSC-derived cells often retain fetal-like metabolic and epigenetic states, limiting their ability to adopt adult activation thresholds. Most organoid cultures cannot sustain matrix architecture, immune organization, or barrier integrity long enough to model slow fibrosis progression or flare–remission cycles, and disease-relevant dynamics such as oscillatory interferon activity rarely emerge spontaneously in vitro. Autoantibody repertoires, which arise from affinity maturation and epitope spreading within germinal center-like ecosystems, are mostly approximated by bulk patient serum. Multi-organ integration, systemic immune circulation, neuroendocrine regulation, reproducibility standards, cost, and throughput all remain unresolved. Yet the trajectory is clear: as biomaterials engineering, stem cell biology, immunology, and computational modeling converge, autoimmune organoids may evolve from descriptive reconstructions into predictive, patient-calibrated microphysiological ecosystems—supporting antifibrotic drug screening for systemic sclerosis, interferon- and complement-targeted strategies for lupus, and combination therapy optimization for rheumatoid arthritis, potentially reducing reliance on animal models along the way.

Subject of Research: Engineering organoid and organ-on-a-chip models of autoimmune diseases for precision medicine

Article Title: Engineering autoimmune disease models using organoids: Harnessing microenvironmental engineering for precision medicine and immunological recapitulation

Article References: Lee, C.-J., Kim, Y., Kim, M., Rim, Y. A., & Ju, J. H. (2026). Engineering autoimmune disease models using organoids: Harnessing microenvironmental engineering for precision medicine and immunological recapitulation. Bioengineering & Translational Medicine, Article e70162. https://doi.org/10.1002/btm2.70162

Image Credits: AI Generated

DOI: 10.1002/btm2.70162

Keywords: organoids, autoimmune disease, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, organ-on-a-chip, microenvironment, iPSC, interferon signaling, fibrosis, precision medicine, extracellular matrix

The study, published in the journal iScience, used induced pluripotent stem cell, or iPSC, lines derived from three healthy male donors aged 27 to 36 and three healthy female donors aged 20 to 49. The researchers guided these stem cells through a developmental journey in a dish: first into mesoderm, then into hemogenic endothelium that produces hematopoietic stem and progenitor cells, and finally into monocytes nurtured with interleukin-3 and macrophage colony-stimulating factor. The monocytes were collected over multiple weeks and cultured further until they matured into macrophages. Crucially, the entire process took place in serum-free medium, which limits exposure to circulating hormones. Because the cells never lived inside a body, any differences that emerged between male-derived and female-derived macrophages could be attributed largely to inherent cellular genetics, namely the chromosomal complement, rather than to years of hormonal and environmental conditioning.

Before any experiments on inflammation, the team verified that their lab-grown macrophages were the real thing. Flow cytometry confirmed expression of the surface markers CD11b, CD14, HLA-DR, and SIRP-alpha, the fingerprint of cells in the myelomonocyte lineage, and immunostaining revealed the pan-macrophage marker CD68. Functional testing showed that the cells could phagocytose fluorescently tagged latex beads, a proxy for their ability to engulf dead cells and debris, and here the sexes performed identically. The same held true when the researchers compared their iPSC-derived macrophages with primary macrophages grown from monocytes isolated from male and female blood donors, supporting the validity of the stem cell model. Migration toward the chemoattractant CXCL12 in a Boyden chamber assay also showed no statistically significant difference between the sexes, although female macrophages trended toward slightly greater movement.

The transcriptome told a subtler story. Bulk RNA sequencing of the resting macrophages, analyzed by principal component analysis and hierarchical clustering, showed that the male lines clustered tightly together while the female lines spread across a much wider range, hinting at hidden variables such as unknown menopausal status among the female donors. Although the first two principal components explained only about 30 percent of the variance, the top 1,000 genes still sorted samples by biological sex rather than by donor, suggesting that sex, not individual identity, was the dominant driver of the transcriptional landscape. When the differentially expressed genes were mapped to their chromosomes, more than half landed on the X and Y chromosomes, a striking signal that sex-linked gene expression underlies much of the baseline dimorphism.

Those baseline genetic differences translated into at least one measurable functional gap. Resting female macrophages secreted significantly more monocyte chemoattractant protein-1, or MCP-1, than their male counterparts. MCP-1 is no bit player; it is a major chemotactic and activating signal that recruits monocytes and macrophages to sites of inflammation, so elevated production by female cells could shape how an inflammatory response unfolds. Female cells also produced slightly higher levels of interleukin-1 beta, IL-6, IL-10, and interferon-alpha 2, while male cells produced somewhat more IL-8, though these differences did not reach statistical significance. Enrichment analysis of the differentially expressed genes flagged pathways including ferroptosis, complement and coagulation cascades, HIF-1 signaling, the cell cycle, and regulation of the actin cytoskeleton, along with gene ontology terms tied to macrophage activation and cytokine production.

The real drama began when the researchers dosed the cells with lipopolysaccharide, or LPS, a component of the outer membrane of Gram-negative bacteria that triggers acute inflammation through toll-like receptor 4 signaling. In the sequencing data, LPS clearly separated stimulated cells from resting controls along one principal axis, and male from female cells along another. The separation between sexes was far more pronounced under inflammation than at rest, indicating that the dimorphism is not merely present but actively amplified by an inflammatory challenge. When the team searched for genes that changed in opposite directions between the sexes, or changed significantly in one sex while remaining flat in the other, the chemokine signaling pathway emerged as the most significantly perturbed, alongside metabolic pathways, cytokine-cytokine receptor interactions, Th1 and Th2 cell differentiation, apoptosis, and extracellular matrix-receptor interactions.

Within the chemokine signaling circuit, the analysis pointed to upregulation of CCL15 and CCL20 and of the signaling intermediates SOS1, SOS2, and BRAF, with downregulation of MAPK3, perturbations expected to cascade through Jak-STAT and MAPK pathways and drive changes in cytokine output, migration, and cell death. Protein-level measurements bore this out in a sex-specific pattern. Both sexes ramped up cytokine production in response to LPS, but the profiles diverged sharply: male macrophages produced significantly more IL-1 beta, TNF-alpha, IL-6, IFN-alpha 2, IL-10, and IL-23, whereas female macrophages produced significantly more IFN-gamma, IL-8, and IL-17A. Notably, these patterns echo published reports from primary human cells, in which men show stronger monocyte-derived cytokine responses to endotoxin, lending physiological credibility to the stem cell model.

Perhaps the most intriguing finding was chromosomal geography. At rest, most differentially expressed genes sat on the sex chromosomes; after LPS, that flipped. Of the 304 genes differentially expressed between male and female macrophages under inflammatory conditions, only 18.1 percent mapped to sex chromosomes, and once baseline differences were accounted for, the sex-linked fraction fell below 3 percent, with the largest share of genes on chromosome 1. The sex-linked genes that did change included X-linked players such as CSTF2, UXT, MBTPS2, HUWE1, and MECP2, upregulated in males, and NOX1, SLC6A8, and TSPYL2, downregulated in males, plus Y-linked shifts in DDX3Y and RPS4Y1. Several of these genes govern NF-kappaB signaling, epigenetic regulation, and reactive oxygen species production, processes with obvious inflammatory stakes. One candidate, the NADPH oxidase NOX1, was confirmed at the protein level: male macrophages produced modestly but significantly more NOX1 protein during inflammation, consistent with prior reports that oxidative stress runs higher in males across species.

The authors are careful about the limits of their work. Six iPSC lines cannot capture the full breadth of human population diversity, and differences between iPSC-derived macrophages and their blood-derived counterparts remain. The single LPS time point misses the dynamic arc of inflammation, and the female donors’ menopausal status, unknown here, may have inflated variability. Still, the model scales naturally through large iPSC banks holding lines from hundreds of donors, and future iterations could embed these macrophages into organ-on-a-chip systems to restore cell-cell interactions lost in isolation. The implications reach into some of medicine’s most stubborn sex disparities, from COVID-19 severity, where cytokine differences between the sexes are well documented, to autoimmune disease, obesity, asthma, cardiovascular disease, and aging. If most inflammation-driven dimorphism is written on the autosomes, steered by epigenetic echoes of the sex chromosomes, then drug developers may need to rethink a long-standing habit: dosing men and women identically on the assumption that their immune cells are interchangeable.

Subject of Research: Sex-based differences in human iPSC-derived macrophage inflammatory responses

Article Title: LPS stimulation reveals male and female dimorphism in human iPSC-derived macrophages

Article References: Graney, P. L., Tavakol, D. N., Lock, R. I., Chen, C., Samaritano, M., Sanchez, E., Hachmann, N. P., Rosales, M. P., Friedman, R., & Vunjak-Novakovic, G. (2026). LPS stimulation reveals male and female dimorphism in human iPSC-derived macrophages. iScience, 29(10), Article 117565. https://doi.org/10.1016/j.isci.2026.117565

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117565

Keywords: macrophages, iPSC, sexual dimorphism, LPS, inflammation, cytokines, sex chromosomes, NOX1, chemokine signaling, immunology, transcriptomics, TLR4

The review’s central message is one of disciplined realism. Atrial fibrosis involves interlinked but distinct changes in stromal-cell state, extracellular matrix turnover, matrix architecture and tissue function. Fibroblast activation and fibroblast-to-myofibroblast transition are prominent features, but the authors stress that neither should be treated as synonymous with established tissue fibrosis, which additionally depends on the amount, composition, organization and persistence of deposited matrix. Fibroblast phenotype is better understood as a continuum, with quiescent, activated, matrix-producing, inflammatory and highly contractile states coexisting and shifting with stimulus, disease stage and culture conditions. Signaling pathways such as TGF-beta/Smad, Wnt/beta-catenin, the renin-angiotensin-aldosterone axis, inflammatory cascades, oxidative stress and Hippo-YAP/TAZ reinforce one another in context-dependent ways, which helps explain why suppressing a single molecular node rarely produces durable matrix or functional recovery.

Equally important, the authors warn that molecular regulation of atrial fibrosis is tissue- and chamber-dependent. Atrial fibroblasts differ from their ventricular counterparts in electrical coupling, mechanosensitivity, metabolic state and ion-channel expression, meaning that findings from ventricular, post-infarction or extracardiac fibrosis models cannot simply be transplanted into the atrial setting. At the tissue level, reactive interstitial fibrosis must be distinguished from replacement fibrosis associated with myocyte loss, and total collagen abundance, fiber orientation, crosslinking and patch size can have very different effects on conduction and mechanical compliance. Clinical imaging adds further ambiguity: late-gadolinium cardiac magnetic resonance and low-voltage mapping identify remodeling-related abnormalities, but the thin atrial wall, spatial resolution limits and threshold-dependent quantification mean imaging-defined fibrosis should be treated as a biomarker, not as a direct histological measurement of collagen or matrix reversal.

To organize the field’s often overclaimed evidence, the review classifies every claim into three categories: directly atrial and AF-specific evidence from human atrial tissue or chamber-validated cells; cardiac but non-atrial evidence from ventricular or generic fibrosis systems; and extrapolated evidence from extracardiac fibrosis, oncology or delivery engineering. The authors also introduce three recurring sources of model-related uncertainty. A mechanism mismatch arises when the experimental stimulus or cell composition fails to reproduce the pathway under study. An endpoint mismatch occurs when reduced collagen staining or molecular suppression is interpreted as tissue-level functional recovery. A safety-context mismatch appears when electrophysiological liability is assessed in healthy or ventricular tissue while the intended therapy targets a remodeled atrial substrate. These categories describe sources of uncertainty rather than proven causes of clinical trial failures, but they give researchers a shared vocabulary for judging whether a model has the capabilities its conclusions require.

Within this framework, patient-derived induced pluripotent stem cells emerge as a powerful but bounded tool. iPSC-derived atrial cardiomyocytes retain the donor’s germline genetic background and can be directed toward atrial identity through timed retinoic-acid exposure and controlled Wnt signaling, with chamber identity confirmed through convergent markers such as NPPA, NR2F2, KCNA5 and GJA5 rather than any single indicator. Yet the review is blunt about limitations: reprogramming and culture attenuate age-related and acquired epigenetic states, and differentiated cells do not automatically reproduce AF duration, obesity, diabetes, inflammation or medication exposure. iPSC-derived atrial cardiomyocytes also remain fetal-like in metabolism, structure and electrophysiology, and maturation interventions can trade adult-like features against variability and throughput. The strongest direct evidence, including work by Seibertz and colleagues showing that tachypacing chamber-validated atrial cardiomyocytes reproduces selected features of AF-associated electrical remodeling, validates only specific claims, not an integrated fibrosis-on-chip platform or patient-specific anti-fibrotic prediction.

The review’s most ambitious proposal is a fit-for-purpose, donor-informed atrial fibrosis microphysiological system built from validated modules. Microengineering can supply anisotropic structure through micropatterned scaffolds, controlled mechanical loading through programmable stretch, and fluidic exposure through endothelialized perfusion, but each capability must be justified against a specific clinical scenario such as pressure-dominant hypertension, volume-dominant valve disease or tachycardia-driven remodeling. Fibroblast provenance is a central design decision: adult primary atrial fibroblasts, iPSC-derived cardiac fibroblasts and commercial primary cardiac fibroblasts are not interchangeable, and the review argues that source, activation state and cardiomyocyte-to-fibroblast ratio must be documented alongside donor metadata including sex, age, AF subtype, comorbidities and clone identity. Representative studies, from Brown and colleagues’ patterned atrial cardiomyocyte-fibroblast cocultures to Reyat and colleagues’ vascularized chamber-specific microtissues showing TGF-beta-driven myofibroblast activation and collagen deposition that responds to receptor inhibition, demonstrate real progress while illustrating how far a fully integrated, mechanically actuated, patient-specific platform still remains.

On the evaluation side, the authors propose tiered high-content phenotyping in which candidates must clear successive gates: molecular target engagement, fibroblast-state modulation, extracellular matrix synthesis and crosslinking, tissue structure and mechanics, electrophysiological function and safety. Microelectrode arrays, voltage and calcium optical mapping, and calibrated force measurements can each provide directly measured endpoints, but higher-level labels such as rhythm stability, reentry suppression or fibrosis reversal require explicit definitions and should never substitute for the underlying data. The review also calls for a shared quality-control matrix across laboratories, specifying minimum reporting items for donor information, differentiation efficiency, device geometry and materials, perfusion and stretch settings, reference pro-fibrotic and anti-fibrotic compounds, and batch-to-batch coefficients of variation. Nominal dose, the authors note, must be distinguished from actual exposure, particularly because device materials such as polydimethylsiloxane can adsorb both small molecules and nanocarriers.

Nanomedicine receives similarly careful treatment. The authors argue that no biologically active payload can modify atrial fibrosis unless adequate unbound exposure reaches the relevant atrial compartment for a sufficient duration, yet direct quantitative evidence for nanoparticle biodistribution in fibrotic human atria is sparse. Delivery route fundamentally changes both opportunity and risk, from intravenous administration that exposes liver, spleen and immune system first, to intracoronary, intracardiac, epicardial or pericardial approaches that improve local concentration while introducing procedural constraints. Particle size, surface chemistry, charge, protein-corona formation and release kinetics jointly shape circulation, penetration and uptake, and dense crosslinked matrix can restrict diffusion, though most quantitative evidence for this barrier comes from hepatic, pulmonary, tumor or cartilage models. Stimulus-responsive release systems and fibroblast-targeting ligands remain promising design principles rather than validated atrial solutions, and one atrial-selective adeno-associated viral vector stands as the clearest demonstration that chamber-biased delivery is biologically achievable.

The review closes with a proposed closed-loop workflow in which delivery measurements inform formulation changes, biological and functional endpoints test mechanistic hypotheses, and safety and uncertainty drive go or no-go decisions, all documented with full traceability. The authors position these platforms as experimental decision-support models, explicitly rejecting the phrase clinical trial in a dish, since no chip reproduces whole-body pharmacokinetics, neurohumoral regulation or clinical outcomes. Artificial intelligence may assist with segmentation, feature extraction and dose-response modeling, but the authors insist on donor-level data splitting, external validation and prospective testing in newly manufactured devices before closed-loop optimization can be considered demonstrated. Their priority list includes multicenter benchmarking with shared controls, direct comparison of fibroblast sources, loading histories mapped to clinical pressure and volume overload, and blinded evaluation of reference compounds. The central opportunity, they conclude, is not a single all-inclusive platform but a transparent evidence chain in which reductionist assays, chamber-specific human atrial models, microphysiological systems, in vivo studies and clinical observations each address a defined uncertainty, moving the field toward therapies that might one day genuinely reverse the structural substrate of atrial fibrillation.

Subject of Research: Patient-specific iPSC models, atrial microphysiological systems and nanomedicine for modeling AF-associated atrial fibrosis

Article Title: Reconstructing AF-associated atrial fibrosis: Patient-specific iPSC models, fit-for-purpose atrial microphysiological systems, and nanomedicine

Article References: Ni, J., Luo, Y., & Guo, R. (2026). Reconstructing AF-associated atrial fibrosis: Patient-specific iPSC models, fit-for-purpose atrial microphysiological systems, and nanomedicine. Materials Today Bio, 40, Article 103633. https://doi.org/10.1016/j.mtbio.2026.103633

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103633

Keywords: atrial fibrillation, atrial fibrosis, iPSC, organ-on-a-chip, microphysiological systems, cardiac fibroblasts, extracellular matrix, nanomedicine, drug delivery, TGF-beta signaling, electrophysiology, atrial cardiomyopathy