Effects of Neurogenin 3 Induction on Endocrine Differentiation and Delamination in Adult Human Pancreatic Ductal Organoids.

IF 2.7 3区 医学 Q1 SURGERY
Transplant International Pub Date : 2025-04-01 eCollection Date: 2025-01-01 DOI:10.3389/ti.2025.13422
Juri Juksar, Rachel Mijdam, Sabine Bosman, Alexander van Oudenaarden, Françoise Carlotti, Eelco J P de Koning
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引用次数: 0

Abstract

Diabetes mellitus is characterized by the loss of pancreatic insulin-secreting β-cells in the Islets of Langerhans. Understanding the regenerative potential of human islet cells is relevant in the context of putative restoration of islet function after damage and novel islet cell replacement therapies. Adult human pancreatic tissue can be cultured as three-dimensional organoids with the capacity for long-term expansion and the promise of endocrine cell formation. Here, we characterize the endocrine differentiation potential of human adult pancreatic organoids. Because exocrine-to-endocrine differentiation is dependent on the expression of Neurogenin 3 (NEUROG3), we first generated NEUROG3-inducible organoid lines. We show that doxycycline-induced NEUROG3 expression in the organoids leads to the formation of chromogranin A positive (CHGA+) endocrine progenitor cells. The efficiency of this differentiation was improved with the addition of thyroid hormone T3 and the AXL inhibitor R428. Further, compound screening demonstrated that modifying the pivotal embryonic endocrine pancreas signalling pathways driven by Notch, YAP, and EGFR led to increased NEUROG3 expression in organoids. In a similar fashion to embryonic development, adult ductal cells delaminated from the organoids after NEUROG3 induction. Thus, mechanisms in islet (re)generation including the initiation of endocrine differentiation and delamination can be achieved by NEUROG3 induction.

神经原素3诱导对成人胰腺导管类器官内分泌分化和分层的影响。
糖尿病的特征是朗格汉斯胰岛中分泌胰岛素的β细胞的减少。了解人类胰岛细胞的再生潜能与假定的损伤后胰岛功能恢复和新的胰岛细胞替代疗法有关。成人胰腺组织可以培养为具有长期扩张能力和内分泌细胞形成前景的三维类器官。在这里,我们描述了人类成人胰腺类器官的内分泌分化潜力。由于外分泌到内分泌的分化依赖于神经原素3 (NEUROG3)的表达,我们首先生成了可诱导NEUROG3的类器官系。我们发现强力霉素诱导的NEUROG3在类器官中的表达导致嗜铬粒蛋白A阳性(CHGA+)内分泌祖细胞的形成。随着甲状腺激素T3和AXL抑制剂R428的加入,这种分化的效率得到提高。此外,化合物筛选表明,修改由Notch、YAP和EGFR驱动的关键胚胎内分泌胰腺信号通路可增加类器官中NEUROG3的表达。与胚胎发育类似,在NEUROG3诱导后,成人导管细胞从类器官剥离。因此,胰岛再生的机制包括启动内分泌分化和分层可以通过诱导NEUROG3来实现。
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来源期刊
Transplant International
Transplant International 医学-外科
CiteScore
4.70
自引率
6.50%
发文量
211
审稿时长
3-8 weeks
期刊介绍: The aim of the journal is to serve as a forum for the exchange of scientific information in the form of original and high quality papers in the field of transplantation. Clinical and experimental studies, as well as editorials, letters to the editors, and, occasionally, reviews on the biology, physiology, and immunology of transplantation of tissues and organs, are published. Publishing time for the latter is approximately six months, provided major revisions are not needed. The journal is published in yearly volumes, each volume containing twelve issues. Papers submitted to the journal are subject to peer review.
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