Author: Jiang, Baoguo ; Yuan, Yusong ; Li, Dongdong ; Dou, Xiaoqiu ; Yang, Kaikai ; Zhang, Peixun ; Wang, Zhengguang ; Xing, Chao ; Feng, Chuan-Liang ; Han, Shuai ; Gao, Laiben ; Tian, Yun

The Schwann cell (SC) is essential in peripheral nerve regeneration by reprogramming into a stem-like "repair Schwann cell" (rSC) phenotype; however, maintaining the rSC stemness remains an unmet challenge. Chirality is a fundamental factor controlling cell fate, and its potential role in regulation of SC reprogramming has long been ignored and remains poorly understood. Herein, inspired by natural chiral components in the SC microenvironment, chiral hydrogel nerve conduits are prepared by supramolecular assembly of l/d-phenylalanine derivatives (l/d-Phe) in polymeric chitosan-gelatin conduits. Right-handed l-Phe fibers within hydrogel conduits maintain the stemness of rSC through enhanced stereoselective interaction between collagen IV and l-Phe fibers triggered by collagen IV-Integrin α1β1, MAPK, and YAP/TAZ signaling pathways and finally activate the key regulator of SC reprogramming, the c-Jun pathway. In the rat model of a sciatic nerve defect, the l-Phe hydrogel nerve conduit significantly enhances nerve regeneration, exhibiting markedly improved histological, electrophysiological, and functional outcomes. The findings reveal the chirality-dependent regulation of SC reprogramming in a pioneering way, offering potential strategies for nerve regeneration therapies.

01 Sep 2024·Osteoarthritis and Cartilage

Do we understand sex-related differences governing dimorphic disease mechanisms in preclinical animal models of osteoarthritis?

Article

Author: Mobasheri, Ali ; Dvir-Ginzberg, Mona ; Maatuf, Yonathan H

Research conducted using murine preclinical models of osteoarthritis (OA) over the last three decades has brought forth many exciting developments showcasing mechanisms and pathways that drive disease pathogenesis. These models have identified therapeutic targets that can be modulated via innovative biologicals and pharmaceuticals. However, many of these approaches have failed to translate to humans and reach the clinic. This commentary aims to highlight some of the key hurdles in the translation of novel findings using preclinical OA models with a focus on sex-related differences and variations in chondrosenescence in these animal models. Notably, besides chondrosenescence, other signaling mechanisms have been shown to be affected by sexual dimorphism (i.e. TGFβ signaling, EGFR/integrin α1β1 and Trpv4). Preclinical models of OA mainly utilize male mice due to their capacity to manifest fast progressing OA structural phenotype compared to female mice. This experimental trend has overlooked and ignored the sex-related effects of numerous mechanisms affecting joint structure, that influence OA structural progression. Future work should focus on analyzing both sexes and understanding sex-related differences, which will enable us to gain a better understanding of the progression of OA based on sex-related mechanistic discrepancies, and potentially improve translatability.

01 Apr 2024·Cancer Research

Osteosarcoma Cells Secrete CXCL14 That Activates Integrin α11β1 on Fibroblasts to Form a Lung Metastatic Niche

Article

Author: Wang, Jin ; Tai, Yi ; Song, YiJiang ; Fu, Jianchang ; Chen, Weiqing ; Song, Guohui ; Wang, Xinliang ; Xu, Yanyang ; Huang, Anfei ; Hu, Jinxin ; Xu, Huaiyuan ; Tang, Qinglian ; Zhu, Xiaojun ; Zeng, Anyu ; Lu, Jinchang ; Chen, Hongmin ; Ma, Jiahui ; Luo, Tianqi ; Chen, Zhihao ; Huang, Shujing ; Gong, Ming ; Feng, Huixiong ; Deng, Chuangzhong

AbstractCooperation between primary malignant cells and stromal cells can mediate the establishment of lung metastatic niches. Here, we characterized the landscape of cell populations in the tumor microenvironment in treatment-naïve osteosarcoma using single-cell RNA sequencing and identified a stem cell–like cluster with tumor cell–initiating properties and prometastatic traits. CXCL14 was specifically enriched in the stem cell–like cluster and was also significantly upregulated in lung metastases compared with primary tumors. CXCL14 induced stromal reprogramming and evoked a malignant phenotype in fibroblasts to form a supportive lung metastatic niche. Binding of CXCL14 to heterodimeric integrin α11β1 on fibroblasts activated actomyosin contractility and matrix remodeling properties. CXCL14-stimulated fibroblasts produced TGFβ and increased osteosarcoma invasion and migration. mAbs targeting the CXCL14-integrin α11β1 axis inhibited fibroblast TGFβ production, enhanced CD8+ T cell–mediated antitumor immunity, and suppressed osteosarcoma lung metastasis. Taken together, these findings identify cross-talk between osteosarcoma cells and fibroblasts that promotes metastasis and demonstrate that targeting the CXCL14-integrin α11β1 axis is a potential strategy to inhibit osteosarcoma lung metastasis.Significance:Cooperation between stem-like osteosarcoma cells and fibroblasts mediated by a CXCL14-integrin α11β1 axis creates a tumor-supportive lung metastatic niche and represents a therapeutic target to suppress osteosarcoma metastasis.

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