Biology subjects

Hoerstrup, S. P.

Publications and source records attributed to Hoerstrup, S. P..

4 recordsLinked to original sources

bioRxiv2026

Targeting integrin αvβ3 by chimeric antigen receptor neural stem cell (CAR-NSC) therapy for stroke

Stroke remains a leading cause of adult disability due to the brains limited regenerative capacity. Although stem cell therapies show favorable safety and feasibility profiles in early clinical trials, poor spatial retention and limited engagement with peri-infarct salvageable tissue constrain efficacy. Here, we engineered human induced pluripotent stem cell-derived neural stem cells (NSC) with a chimeric antigen receptor (CAR)-like architecture to enable targeted recognition of injury-associated cues. Specifically, cells were modified to express a membrane-anchored single chain variable fragment (scFv) targeting integrin v{beta}3, a receptor selectively upregulated in peri-infarct vasculature after stroke. Engineered CAR-NSC retained progenitor identity and selectively bound recombinant integrin v{beta}3 in vitro. Following focal transplantation into a photothrombotic stroke mouse model, CAR-NSC displayed broader dispersion within peri-infarct tissue and covered a greater proportion of the ischemic lesion compared to non-binding control-CAR-NSC. CAR-NSC grafts extended longer neurites that aligned more closely with the lesion border. In addition, CAR-NSC transplantation reduced microglial activation and was associated with increased vascular density and blood-brain barrier integrity in the peri-infarct zone. Together, these findings establish a CAR-like NSC strategy for stroke to direct the spatial distribution and tissue engagement of transplanted cells. Molecular targeting of injury-associated cues may improve the precision and regenerative efficacy of cell-based therapies for stroke and related neurological disorders.

neuroscience↗

bioRxiv2025

Generation of Valvular Interstitial Cells from Human Pluripotent Stem Cells

Heart valves are living structures whose sophisticated functions are mediated by a specialized population of mesenchymal cells known as valvular interstitial cells (VICs). Given their central role in valve homeostasis, VICs represent a promising cell population for studying heart valve diseases and developing novel therapies to treat them. Here, we describe a strategy for generating VICs from human pluripotent stem cells (hPSCs) by stage-specific manipulation of developmental signalling pathways. Our results demonstrate that hPSC-derived VICs show a high transcriptional similarity to primary human fetal VICs and can secrete key proteins of the valve extracellular matrix. We further investigate the heterogeneity of hPSC-derived VICs and identify two major subpopulations with distinct molecular and functional properties, mirroring the cellular diversity observed in vivo. Finally, we utilize an in vitro model of Noonan syndrome to demonstrate that hPSC-derived VICs can accurately recapitulate key aspects of valve disease. Collectively, these findings provide a reproducible method for the scaled generation of bona fide hPSC-derived VICs and establish their utility in disease modelling and tissue engineering applications. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABS- We established a robust platform to generate bona fide valvular interstitial cells (VICs) from human pluripotent stem cells (hPSCs), recapitulating native VIC identity and function. - We delineated signaling pathways that promote the development of two distinct VIC subsets and identified a surface marker to distinguish between them. What are the clinical implications?- A renewable, human-specific source of VICs enables precise mechanistic studies of valve development and disease that are not possible with limited surgical specimens or animal models. - This platform creates opportunities for therapeutic applications, including drug discovery and tissue engineering approaches for valve repair.

cell biology↗

bioRxiv2022

Xeno-free induced pluripotent stem cell-derived neural progenitor cells for in vivo applications

Cell-based therapies are a promising treatment paradigm for neurodegenerative diseases and other brain injuries. Despite recent advances in stem cell technology, major concerns have been raised regarding the feasibility and safety of cell therapies for clinical applications. Here, we generate good manufacturing practice (GMP)-compatible neural progenitor cells (NPCs) from transgene- and xeno-free induced pluripotent stem cells (iPSCs) that can be smoothly adapted for clinical applications. The produced NPCs have a stable gene-expression over at least 15 passages and can be scaled for up to 1018 cells per initially seeded 106 cells. To ensure a pure NPC population for in vivo applications, we reduce risks of iPSC contamination using micro RNA-switch technology as a safety checkpoint. Using lentiviral transduction with a fluorescent and bioluminescent dual-reporter construct, combined with non-invasive in vivo bioluminescent imaging, we longitudinally tracked the grafted cells in healthy wild-type and genetically immunosuppressed mice as well as in a mouse model of ischemic stroke. Long term in-depth characterization revealed that transplanted cells have the capability to survive and spontaneously differentiate into functional and mature neurons throughout a time course of a month.

neuroscience↗

bioRxiv2020

Human induced pluripotent stem cell-derived arteries as personalized models of atherosclerosis on-a-chip

Atherosclerosis is an arterial disease characterized by intravascular plaques. Disease hallmarks are vessel stenosis and hyperplasia, eventually escalating into plaque rupture and acute clinical presentations. Innate immune cells and local variations in hemodynamics are core players in the pathology, but their mutual relationship has never been investigated before due to the lack of modeling systems with adequate degree of complexity. Here, we combined computational fluid dynamics and tissue-engineering to achieve, for the first time in vitro, full atherosclerotic plaque development. Our model incorporates induced pluripotent stem cell-derived populations into small-caliber arteries that are cultured in atheroprone conditions. Using machine-learning-aided immunophenotyping, molecular and nanoprobe-based tensile analyses, we found that immune cells, extracellular matrix components and tensional state were comparable between in vitro and ex vivo human lesions. Our results provide further insights into the relation between hemodynamics and inflammation, introducing a versatile, scalable modeling tool to study atherosclerosis onset and progression.

bioengineering↗