Scientists Grow Living Human Skin With Blood Vessels and Working Immune Cells in the Lab

Human skin is far more than a simple wrapping around the body. It is a layered, living ecosystem in which a stratified epidermis, a fibroblast-rich dermis and a dynamic network of blood vessels work together with immune cells to defend against the outside world. When this system breaks down, the result is often inflammatory disease, and atopic dermatitis alone affects hundreds of millions of people worldwide. Yet researchers have long struggled to study these processes in a genuinely human context, because conventional laboratory models strip away exactly the features that matter most: vasculature and immunity. A new study published in Experimental & Molecular Medicine now reports a way to rebuild much of that complexity in a dish, using modularly assembled stem-cell-derived tissues that grow blood vessels, mount allergic inflammatory responses and respond to clinically approved drugs.

The research team, led by Min-Ji Kim and Kyung-Sun Kang of Seoul National University together with Seunghee Lee, created what they call vascularized skin assembloids, or VSAs. The strategy builds on two earlier stem-cell technologies. Skin organoids grown from human induced pluripotent stem cells can recapitulate epidermal and dermal differentiation and even generate appendages such as hair follicles, melanocytes and neurons. Blood vessel organoids, likewise derived from pluripotent stem cells, self-assemble into endothelial networks with lumina and mural support cells. Each system on its own, however, falls short of real skin. Skin organoids often develop inverted polarity, with the epidermis facing inward, and can undergo ectopic cartilage formation, while neither model on its own provides the vascular and immune components needed to model inflammation.

The assembloid approach sidesteps these problems by treating the two organoid types as building blocks rather than finished products. The researchers first optimized the extracellular matrix in which the blood vessel organoids were embedded, testing different ratios of Matrigel to collagen. Expression of the endothelial genes PECAM1 and CDH5, markers of vascular density and junctional organization, peaked at a one-to-three Matrigel-to-collagen ratio, while alpha-SMA, a marker of aberrant mural-cell activation, rose in collagen-rich matrices. With this optimized composition in hand, the team cut mature, cyst-like skin organoids into eight pieces each and placed them onto pre-vascularized matrix, then cultured the combined tissues at an air–liquid interface for several weeks.

Over 28 days, the fused structures underwent a striking transformation. Initially the skin organoid fragments and vascular matrix retained distinct boundaries, but within a week the skin tissue spread across the vascularized surface. By day 15 the construct had thickened and consolidated, and by day 28 branched CD31-positive vascular networks had arborized extensively through the dermal compartment. Gene-expression analysis tracked this maturation, with PECAM1 and CDH5 rising steadily while the barrier genes filaggrin and loricrin were significantly upregulated by the end of the culture period. Three-dimensional reconstructions showed that the vascular networks maintained relatively uniform vessel diameters, and hair-follicle-like structures were frequently found sitting adjacent to vessels, echoing the intimate spatial relationship between skin appendages and blood supply in native tissue. The vascularized constructs also secreted more vascular endothelial growth factor and nitric oxide than non-vascularized controls, indicating genuine endothelial activity rather than passive decoration.

Single-cell RNA sequencing confirmed that the assembloids had gained cellular complexity, not just structural features. Compared with conventional skin organoids, VSAs contained increased proportions of cells expressing endothelial markers such as PECAM1, CDH5, KDR, VWF and CLDN5, as well as perivascular markers including PDGFRB, RGS5 and ACTA2. Enrichment analysis of genes upregulated in the assembloids pointed to programs of endothelial proliferation and migration, vasculature development, angiogenesis, basement membrane organization and cytokine response. Histology reinforced the picture: the assembloids developed a defined KRT5-positive basal layer and KRT10-positive suprabasal layer, expressed filaggrin and loricrin more prominently than ordinary skin organoids, and restricted penetration of Lucifer Yellow dye largely to the outer epidermis, evidence of a more mature barrier. When transplanted onto wounds in immunodeficient mice, the grafts persisted for four weeks, and their human CD31-positive vessels connected with mouse host vasculature and became accessible to an intravenously injected lectin, suggesting the engineered vessels can be incorporated into a living circulatory system.

The most consequential addition, however, was immunological. The team incorporated mononuclear cells isolated from umbilical cord blood into the assembloids and challenged the system with lipopolysaccharide, a bacterial endotoxin. In vascularized constructs, the immune cells migrated into the upper dermis and clustered near CD31-positive vascular structures, whereas in matched avascular organoids the infiltrating cells rarely progressed beyond the lower dermis. Molecular readouts told the same story: after LPS stimulation, vascularized assembloids with immune cells showed markedly higher expression of the adhesion molecules ICAM1 and VCAM1 and the inflammatory cytokines IL-6 and TNF-alpha than any other condition, with ICAM1 upregulation localized to the endothelial structures themselves. In other words, the vasculature was not merely a passive conduit but an active participant in recruiting and activating immune cells, exactly as it does in inflamed human skin.

With an immune-responsive, vascularized skin model in hand, the researchers turned to atopic dermatitis. They applied house dust mite extract, a major environmental allergen, to the epidermal surface of the assembloids in three treatments spaced two days apart. The response was dramatic and reproducible. Transcriptomic profiling separated treated and control samples cleanly, revealing activation of inflammatory, cornification and type 2 immune-regulation programs, along with TNF and IL-17 signalling pathways. Crucially, when the team compared their treated assembloids with published gene-expression data from skin biopsies of atopic dermatitis patients, the patterns partially paralleled each other: both showed elevated type 2 and alarmin-associated genes such as IL33, IL4R, CCL17 and CCL26, keratinocyte stress markers including KRT16, S100A8 and S100A9, and adhesion and infiltration mediators such as CXCL8 and ICAM1. At the tissue level, allergen exposure thickened the epidermis, reduced filaggrin, raised KRT16 and drove immune cells along vascular structures into the upper dermis. Flow cytometry identified CD4-positive and CD8-positive T cells, CD14-positive myeloid cells and CD11c-positive HLA-DR-positive antigen-presenting-like populations, with a rightward shift in HLA-DR intensity suggesting myeloid activation. The treated assembloids also secreted elevated levels of TSLP, CCL17, IL-4, IL-13, VEGF and nitric oxide.

The final test was pharmacological, and here the model passed with a precision that will excite drug developers. The team applied upadacitinib, a JAK1 inhibitor, and dupilumab, an antibody that blocks the IL-4 receptor alpha subunit, two drugs with proven efficacy in moderate-to-severe atopic dermatitis. Both agents reduced allergen-induced epidermal hyperplasia, restored expression of the barrier proteins filaggrin, loricrin and claudin-1, suppressed TSLP and KRT16, and reduced the infiltration of CD4-positive T cells into the upper dermis. Mechanistically, house dust mite exposure strongly increased phosphorylation of STAT6, the central transcription factor downstream of IL-4 and IL-13 signalling, and both drugs significantly diminished this activation, along with the expression of STAT6 target genes including TARC, MDC, CCL26 and POSTN. Cytokine profiling showed broad suppression of the allergen-induced mediators IL-33, ST2, IL-4, IL-13, CCL17, RANTES, VCAM1 and VEGF. The responses matched the known mechanisms of action of both therapeutics, which is precisely what a preclinical screening platform should do.

The authors are candid about the limits of their system. The vascular networks, while organized and associated with basement membrane and perivascular cells, do not yet form a fully mature, perfusable artery-vein-capillary hierarchy, because the static air–liquid culture lacks blood flow and haemodynamic cues; integrating microfluidic perfusion could change that. Definitive lymphatic vessels were not observed, the immune compartment derives from cord blood rather than skin-resident cells and lacks bona fide Langerhans cells and tissue-resident memory T cells, and the allergen model captures an acute response rather than the chronic, relapsing reality of clinical atopic dermatitis. Even so, the achievement is substantial: a modular, human-cell-derived skin model that assembles epithelium, dermis, vessels and immune cells in a tunable way, reproduces key molecular features of a common allergic disease, and responds to real drugs in a mechanism-consistent manner. Beyond disease modelling, the preformed vascular networks suggest future roles in regenerative medicine, from wound healing to bioengineered skin grafts, where vascularization remains the central bottleneck. For a field long forced to choose between oversimplified dishes and imperfect animal models, vascularized skin assembloids offer a third option that looks increasingly like the real thing.

Subject of Research: Vascularized, immune-integrated human skin assembloids for modelling atopic dermatitis and drug testing in vitro

Article Title: Vascularized human skin assembloids model compartmental skin organization and immune responsiveness in vitro

Article References: Kim, M.-J., Lee, S., & Kang, K.-S. (2026). Vascularized human skin assembloids model compartmental skin organization and immune responsiveness in vitro. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01840-x

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01840-x

Keywords: skin assembloids, organoids, atopic dermatitis, vascularization, immune cells, house dust mite, upadacitinib, dupilumab, STAT6 signalling, induced pluripotent stem cells, skin barrier, inflammatory skin disease