Lee Sangmin, Lee Jeongbok, Kwon Hyunseok, Shin Heungsoo
Department of Bioengineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Bioact Mater. 2025 Feb 18;48:171-188. doi: 10.1016/j.bioactmat.2025.02.024. eCollection 2025 Jun.
Adipose tissue is highly vascularized, which is crucial for homeostasis and energy storage. Current efforts to engineer 3D vascularized adipose tissue typically involve co-culturing adipocytes and endothelial cells, but adipogenic differentiation often suppresses endothelial function. In this study, we propose a novel approach to reconstruct vascularized adipose tissues by effectively coupling adipogenesis and vasculogenesis. First, we developed adipo-inductive nanofibers (ID/F@INS) that contain indomethacin and insulin. The adipogenesis of human adipose-derived stem cells (hADSCs) in general medium was significantly enhanced in adipogenic spheroids (AS) prepared with hADSCs and ID/F@INS, which were encapsulated in a gelatin methacryloyl (GelMA) hydrogel. To further replicate clustering during adipogenesis, we generated AS of varying sizes and found that larger spheroids exhibited markedly greater adipogenesis than smaller ones. At the same time, we used hADSCs and human umbilical vein endothelial cells to generate vascular spheroids (VS). The biomimetic integration of AS and VS within GelMA hydrogels enabled us to investigate the interactions between adipogenesis and vascularization. The integration of the two types of spheroids (VS:AS ratio of 2:1) significantly improved vascular network formation, indicating the concurrent stimulation of adipogenesis and vasculogenesis. This system was then applied to develop an obesity-like white adipose dysfunction model characterized by reduced vascularization and the elevated expression of pro-inflammatory cytokines. In addition, we found both vascularization and adipogenesis when we implanted the engineered tissue into mice, demonstrating the potential of our tissue for therapeutic applications in tissue reconstruction.
脂肪组织血管高度丰富，这对体内平衡和能量储存至关重要。目前构建三维血管化脂肪组织的努力通常涉及脂肪细胞和内皮细胞的共培养，但脂肪生成往往会抑制内皮功能。在本研究中，我们提出了一种通过有效耦合脂肪生成和血管生成来重建血管化脂肪组织的新方法。首先，我们开发了含有吲哚美辛和胰岛素的脂肪诱导纳米纤维（ID/F@INS）。在用ID/F@INS和人脂肪来源干细胞（hADSCs）制备的脂肪生成球体（AS）中，hADSCs在普通培养基中的脂肪生成在包裹于甲基丙烯酰化明胶（GelMA）水凝胶中时显著增强。为了进一步模拟脂肪生成过程中的聚集，我们生成了不同大小的AS，发现较大的球体比较小的球体表现出明显更强的脂肪生成。同时，我们用hADSCs和人脐静脉内皮细胞生成血管球体（VS）。GelMA水凝胶中AS和VS的仿生整合使我们能够研究脂肪生成和血管生成之间的相互作用。两种类型球体的整合（VS:AS比例为2:1）显著改善了血管网络的形成，表明同时刺激了脂肪生成和血管生成。然后将该系统应用于开发一种以血管化减少和促炎细胞因子表达升高为特征的肥胖样白色脂肪功能障碍模型。此外，当我们将工程化组织植入小鼠体内时，我们发现了血管生成和脂肪生成，证明了我们的组织在组织重建治疗应用中的潜力。
