Directed differentiation of human mesenchymal stromal cells into functional endothelial cells having IKAROS-mediated immune tolerance properties

Jung-Kyu Han¹, Haena Lee², Dasom Shin², Youngchul Shin², HanJun Oh³, Seyoon Lee³, Seong Keun Kwon⁴, Minseop Kim⁵, Ju-Hee Kim⁵, Seok Chung⁶, Jong-Il Kim⁷, Hyo-Soo Kim⁸

Affiliations

¹ Department of Internal Medicine, Seoul National University College of Medicine, South Korea; Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, South Korea.
² Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea.
³ Genomic Medicine Institute, Medical Research Center, Seoul National University, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, South Korea.
⁴ Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, South Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Cancer Research Institute, Seoul National University, South Korea; Sensory Organ Research Institute, Seoul National University Medical Research Center, South Korea.
⁵ KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, South Korea.
⁶ KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, South Korea; School of Mechanical Engineering, Korea University, South Korea; Center for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
⁷ Genomic Medicine Institute, Medical Research Center, Seoul National University, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, South Korea. Electronic address: jongil@snu.ac.kr.
⁸ Department of Internal Medicine, Seoul National University College of Medicine, South Korea; Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, South Korea. Electronic address: hyosoo@snu.ac.kr.

PMID: 40818327
DOI: 10.1016/j.biomaterials.2025.123606

Directed differentiation of human mesenchymal stromal cells into functional endothelial cells having IKAROS-mediated immune tolerance properties

Jung-Kyu Han et al. Biomaterials. 2026 Feb.

. 2026 Feb:325:123606.

doi: 10.1016/j.biomaterials.2025.123606. Epub 2025 Aug 8.

Authors

Jung-Kyu Han¹, Haena Lee², Dasom Shin², Youngchul Shin², HanJun Oh³, Seyoon Lee³, Seong Keun Kwon⁴, Minseop Kim⁵, Ju-Hee Kim⁵, Seok Chung⁶, Jong-Il Kim⁷, Hyo-Soo Kim⁸

Affiliations

¹ Department of Internal Medicine, Seoul National University College of Medicine, South Korea; Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, South Korea.
² Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea.
³ Genomic Medicine Institute, Medical Research Center, Seoul National University, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, South Korea.
⁴ Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, South Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Cancer Research Institute, Seoul National University, South Korea; Sensory Organ Research Institute, Seoul National University Medical Research Center, South Korea.
⁵ KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, South Korea.
⁶ KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, South Korea; School of Mechanical Engineering, Korea University, South Korea; Center for Brain Technology, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
⁷ Genomic Medicine Institute, Medical Research Center, Seoul National University, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea; Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, South Korea. Electronic address: jongil@snu.ac.kr.
⁸ Department of Internal Medicine, Seoul National University College of Medicine, South Korea; Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, South Korea. Electronic address: hyosoo@snu.ac.kr.

PMID: 40818327
DOI: 10.1016/j.biomaterials.2025.123606

Abstract

We report an efficient method for the directed differentiation of mesenchymal stromal cells derived from embryonic stem cells (EMSCs) into functional endothelial cells (EC), addressing the challenges of direct conversion, such as cellular senescence. We found that transduction of one transcription factor, ER71, was required for the efficient derivation of induced endothelial cells from EMSCs (MiECs). Addition of transforming growth factor-β inhibitor (SB431542), vascular endothelial growth factor, and ascorbic acid to the culture media enhanced the differentiation efficiency. After one week of the induction protocol, 75.4 ± 4.5 % of EMSCs were directly differentiated into ECs as defined by double-positivity for VE-cadherin/PECAM1. MiECs demonstrated endothelial characteristics and functions. Interestingly, the immune tolerance of MSCs was potentiated in MiECs, and were mediated by IKAROS, a direct transcriptional target of ER71. We established an efficient protocol for direct differentiation of MSCs into functional ECs with immune tolerance properties based on ER71 transduction. This technology provides the allogenic cell source for ready-to-use cell therapies for diseases or conditions requiring vascularization.

Keywords: Directed differentiation; Endothelial cells; IKAROS; Immune tolerance; Mesenchymal stromal cell.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Directed differentiation of human mesenchymal stromal cells into functional endothelial cells having IKAROS-mediated immune tolerance properties

Affiliations

Directed differentiation of human mesenchymal stromal cells into functional endothelial cells having IKAROS-mediated immune tolerance properties

Authors

Affiliations

Abstract

Conflict of interest statement

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Substances

LinkOut - more resources

Full Text Sources

Miscellaneous