Transplantation of in vitro prefabricated adipose organoids attenuates skin fibrosis by restoring subcutaneous fat and inducing dermal adipogenesis
Transplantation of in vitro prefabricated adipose organoids attenuates skin fibrosis by restoring subcutaneous fat and inducing dermal adipogenesis
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DOI：
10.1096/fj.202202117r
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发表时间：
2023-07
期刊：
影响因子：
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通讯作者：
Yuping Quan;Yuteng Zhang;Jian Li;F. Lu;Junrong Cai
中科院分区：
文献类型：
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作者：
Yuping Quan;Yuteng Zhang;Jian Li;F. Lu;Junrong Cai
局限性硬皮病是一种复杂的自身免疫性疾病，其特征是真皮纤维化和皮肤脂肪丢失。虽然细胞疗法提供了一种有前途的治疗选择，但干细胞移植导致存活率低且靶细胞分化失败。在这项研究中，我们的目的是通过三维（3D）培养使用微血管碎片（MVF）预制同基因脂肪类器官（ad-organoids），并将其移植到纤维化皮肤下，以恢复皮下脂肪并逆转局部硬皮病的病理表现。我们采用 3D 培养同基因 MVF 并逐步诱导血管生成和脂肪生成来生产广告类器官，并在体外评估其微观结构和旁分泌功能。用脂肪源干细胞（ASC）、脂肪细胞、ad-类器官和基质胶治疗诱导皮肤硬皮病的 C57/BL6 小鼠，并通过组织学评估治疗效果。我们的结果表明，源自 MVF 的广告类器官含有成熟的脂肪细胞和完善的血管网络，分泌多种脂肪因子，促进 ASC 的成脂分化，并抑制硬皮病成纤维细胞的增殖和迁移。 Ad类器官的皮下移植重建了博莱霉素诱导的硬皮病皮肤的皮下脂肪层并刺激真皮脂肪细胞再生。它减少胶原沉积和真皮厚度，减轻真皮纤维化。此外，ad-类器官抑制巨噬细胞浸润并促进皮损中的血管生成。总之，MVF 的 3D 培养和逐步血管生成和脂肪生成诱导是制造 ad 类器官的有效策略，预制的 ad 类器官的移植可以通过恢复皮肤脂肪和减轻皮肤纤维化来改善皮肤硬化。这些发现为治疗局部硬皮病提供了一种有前途的治疗方法。
Localized scleroderma is a complex autoimmune disease characterized by dermal fibrosis and loss of cutaneous fat. While cytotherapy offers a promising treatment option, stem cell transplantation results in low survival rates and fails in target cell differentiation. In this study, we aimed to prefabricate syngeneic adipose organoids (ad‐organoids) using microvascular fragments (MVFs) via three‐dimensional (3D) culturing and transplant them beneath the fibrotic skin to restore subcutaneous fat and reverse the pathological manifestation of localized scleroderma. We employed 3D culturing of syngeneic MVFs with stepwise angiogenic and adipogenic induction to produce ad‐organoids and evaluated their microstructure and paracrine function in vitro. C57/BL6 mice with induced skin scleroderma were treated with adipose‐derived stem cells (ASCs), adipocytes, ad‐organoids, and Matrigel, and the therapeutic effect was assessed histologically. Our results showed that ad‐organoids derived from MVF contained mature adipocytes and a well‐established vessel network, secreted multiple adipokines, promoted adipogenic differentiation of ASCs, and suppressed proliferation and migration of scleroderma fibroblasts. Subcutaneous transplantation of ad‐organoids reconstructed the subcutaneous fat layer and stimulated dermal adipocyte regeneration in bleomycin‐induced scleroderma skin. It reduced collagen deposition and dermal thickness, attenuating dermal fibrosis. Moreover, ad‐organoids suppressed macrophage infiltration and promoted angiogenesis in the skin lesion. In conclusion, 3D culturing of MVFs with stepwise angiogenic and adipogenic induction is an effective strategy for the fabrication of ad‐organoids, and the transplantation of prefabricated ad‐organoids can improve skin sclerosis by restoring cutaneous fat and attenuating skin fibrosis. These findings offer a promising therapeutic approach for the treatment of localized scleroderma.