Self-organized insulin-producing β-cells differentiated from human omentum-derived stem cells and their in vivo therapeutic potential.

IF 11.3 1区 医学 Q1 Medicine Biomaterials Research Pub Date : 2023-08-29 DOI:10.1186/s40824-023-00419-1
Ji Hoon Jeong, Ki Nam Park, Joo Hyun Kim, KyungMu Noh, Sung Sik Hur, Yunhye Kim, Moonju Hong, Jun Chul Chung, Jae Hong Park, Jongsoon Lee, Young-Ik Son, Ju Hun Lee, Sang-Heon Kim, Yongsung Hwang
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Abstract

Background: Human omentum-derived mesenchymal stem cells (hO-MSCs) possess great potential to differentiate into multiple lineages and have self-renewal capacity, allowing them to be utilized as patient-specific cell-based therapeutics. Although the use of various stem cell-derived β-cells has been proposed as a novel approach for treating diabetes mellitus, developing an efficient method to establish highly functional β-cells remains challenging.

Methods: We aimed to develop a novel cell culture platform that utilizes a fibroblast growth factor 2 (FGF2)-immobilized matrix to regulate the adhesion and differentiation of hO-MSCs into insulin-producing β-cells via cell-matrix/cell-cell interactions. In our study, we evaluated the in vitro differentiation potential of hO-MSCs cultured on an FGF2-immobilized matrix and a round-bottom plate (RBP). Further, the in vivo therapeutic efficacy of the β-cells transplanted into kidney capsules was evaluated using animal models with streptozotocin (STZ)-induced diabetes.

Results: Our findings demonstrated that cells cultured on an FGF2-immobilized matrix could self-organize into insulin-producing β-cell progenitors, as evident from the upregulation of pancreatic β-cell-specific markers (PDX-1, Insulin, and Glut-2). Moreover, we observed significant upregulation of heparan sulfate proteoglycan, gap junction proteins (Cx36 and Cx43), and cell adhesion molecules (E-cadherin and Ncam1) in cells cultured on the FGF2-immobilized matrix. In addition, in vivo transplantation of differentiated β-cells into animal models of STZ-induced diabetes revealed their survival and engraftment as well as glucose-sensitive production of insulin within the host microenvironment, at over 4 weeks after transplantation.

Conclusions: Our findings suggest that the FGF2-immobilized matrix can support initial cell adhesion, maturation, and glucose-stimulated insulin secretion within the host microenvironment. Such a cell culture platform can offer novel strategies to obtain functional pancreatic β-cells from patient-specific cell sources, ultimately enabling better treatment for diabetes mellitus.

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自组织胰岛素生成β细胞从人网膜来源干细胞分化及其体内治疗潜力。
背景:人类大网膜来源的间充质干细胞(hO-MSCs)具有巨大的分化成多谱系和自我更新能力的潜力,使它们能够被用于患者特异性细胞治疗。尽管各种干细胞衍生的β细胞已被提出作为治疗糖尿病的一种新方法,但开发一种有效的方法来建立高功能的β细胞仍然具有挑战性。方法:我们旨在开发一种新的细胞培养平台,利用成纤维细胞生长因子2 (FGF2)固定基质,通过细胞-基质/细胞-细胞相互作用调节hO-MSCs的粘附和分化为产生胰岛素的β细胞。在我们的研究中,我们评估了在fgf2固定基质和圆底板(RBP)上培养的hO-MSCs的体外分化潜力。此外,采用链脲佐菌素(STZ)诱导的糖尿病动物模型,评估β-细胞移植到肾胶囊中的体内治疗效果。结果:我们的研究结果表明,在fgf2固定基质上培养的细胞可以自组织成产生胰岛素的β细胞祖细胞,这从胰腺β细胞特异性标记物(PDX-1、胰岛素和Glut-2)的上调中可以看出。此外,我们观察到在fgf2固定基质上培养的细胞中,硫酸肝素蛋白聚糖、间隙连接蛋白(Cx36和Cx43)和细胞粘附分子(E-cadherin和Ncam1)显著上调。此外,将分化的β-细胞体内移植到stz诱导的糖尿病动物模型中,在移植后4周多的时间里,β-细胞在宿主微环境中存活、植入并产生葡萄糖敏感的胰岛素。结论:我们的研究结果表明,fgf2固定的基质可以支持宿主微环境中初始细胞的粘附、成熟和葡萄糖刺激的胰岛素分泌。这种细胞培养平台可以提供从患者特异性细胞来源获得功能性胰腺β细胞的新策略,最终实现更好的糖尿病治疗。
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来源期刊
Biomaterials Research
Biomaterials Research Medicine-Medicine (miscellaneous)
CiteScore
10.20
自引率
3.50%
发文量
63
审稿时长
30 days
期刊介绍: Biomaterials Research, the official journal of the Korean Society for Biomaterials, is an open-access interdisciplinary publication that focuses on all aspects of biomaterials research. The journal covers a wide range of topics including novel biomaterials, advanced techniques for biomaterial synthesis and fabrication, and their application in biomedical fields. Specific areas of interest include functional biomaterials, drug and gene delivery systems, tissue engineering, nanomedicine, nano/micro-biotechnology, bio-imaging, regenerative medicine, medical devices, 3D printing, and stem cell research. By exploring these research areas, Biomaterials Research aims to provide valuable insights and promote advancements in the biomaterials field.
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