2. Academic Validation
  3. LINC MIR503HG Controls SC-β Cell Differentiation and Insulin Production by Targeting CDH1 and HES1

LINC MIR503HG Controls SC-β Cell Differentiation and Insulin Production by Targeting CDH1 and HES1

  • Adv Sci (Weinh). 2024 Jan 20:e2305631. doi: 10.1002/advs.202305631.
Yang Xu 1 2 3,  Susu Mao 4,  Haowen Fan 1 3,  Jian Wan 1 3,  Lin Wang 1 5,  Mingyu Zhang 6,  Shajun Zhu 1,  Jin Yuan 7,  Yuhua Lu 1,  Zhiwei Wang 1,  Bin Yu 4,  Zhaoyan Jiang 2,  Yan Huang 1 3 4
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
  • 2 Center of Gallbladder Disease, Shanghai East Hospital, Institute of Gallstone Disease, School of Medicine, Tongji University, Shanghai, 200092, China.
  • 3 Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
  • 4 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
  • 5 Department of Graduate School, Dalian Medical University, Dalian, Liaoning, 116000, China.
  • 6 Department of Nuclear Medicine, Beijing Friendship Hospital, Affiliated to Capital Medical University, Beijing, 100050, China.
  • 7 Department of Endocrinology and Metabolism, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
PMID: 38243869 DOI: 10.1002/advs.202305631
Abstract

Stem cell-derived pancreatic progenitors (SC-PPs), as an unlimited source of SC-derived β (SC-β) cells, offers a robust tool for diabetes treatment in stem cell-based transplantation, disease modeling, and drug screening. Whereas, PDX1+ /NKX6.1+ PPs enhances the subsequent endocrine lineage specification and gives rise to glucose-responsive SC-β cells in vivo and in vitro. To identify the regulators that promote induction efficiency and cellular function maturation, single-cell RNA-sequencing is performed to decipher the transcriptional landscape during PPs differentiation. The comprehensive evaluation of functionality demonstrated that manipulating LINC MIR503HG using CRISPR in PP cell fate decision can improve Insulin synthesis and secretion in mature SC-β cells, without effects on liver lineage specification. Importantly, transplantation of MIR503HG-/- SC-β cells in recipients significantly restored blood glucose homeostasis, accompanied by serum C-peptide release and an increase in body weight. Mechanistically, by releasing CtBP1 occupying the CDH1 and HES1 promoters, the decrease in MIR503HG expression levels provided an excellent extracellular niche and appropriate Notch signaling activation for PPs following differentiation. Furthermore, this exhibited higher crucial transcription factors and mature epithelial markers in CDH1High expressed clusters. Altogether, these findings highlighted MIR503HG as an essential and exclusive PP cell fate specification regulator with promising therapeutic potential for patients with diabetes.

Keywords

differentiation; human pluripotent stem cells; lncRNA; pancreatic progenitors; scRNA-seq.

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