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Calorie restriction and rapamycin distinctly restore non-canonical ORF translation in the muscles of aging mice 卡路里限制和雷帕霉素可明显恢复衰老小鼠肌肉中的非规范 ORF 翻译
IF 7.2 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-09-19 DOI: 10.1038/s41536-024-00369-9
Nitish Mittal, Meric Ataman, Lionel Tintignac, Daniel J. Ham, Lena Jörin, Alexander Schmidt, Michael Sinnreich, Markus A. Ruegg, Mihaela Zavolan

Loss of protein homeostasis is one of the hallmarks of aging. As such, interventions that restore proteostasis should slow down the aging process and improve healthspan. Two of the most broadly used anti-aging interventions that are effective in organisms from yeast to mammals are calorie restriction (CR) and rapamycin (RM) treatment. To identify the regulatory mechanisms by which these interventions improve the protein homeostasis, we carried out ribosome footprinting in the muscle of mice aged under standard conditions, or under long-term treatment with CR or RM. We found that the treatments distinctly impact the non-canonical translation, RM primarily remodeling the translation of upstream open reading frames (uORFs), while CR restores stop codon readthrough and the translation of downstream ORFs. Proteomics analysis revealed the expression of numerous non-canonical ORFs at the protein level. The corresponding peptides may provide entry points for therapies aiming to maintain muscle function and extend health span.

蛋白质失去平衡是衰老的标志之一。因此,恢复蛋白质稳态的干预措施应能延缓衰老过程并改善健康寿命。卡路里限制(CR)和雷帕霉素(RM)治疗是在从酵母到哺乳动物的生物体中最广泛使用的两种有效的抗衰老干预措施。为了确定这些干预措施改善蛋白质平衡的调控机制,我们在标准条件下或长期接受雷帕霉素或雷帕霉素治疗的老龄小鼠肌肉中进行了核糖体足迹分析。我们发现,这两种治疗方法对非规范翻译产生了明显的影响,RM主要重塑了上游开放阅读框(uORF)的翻译,而CR则恢复了终止密码子的读取和下游ORF的翻译。蛋白质组学分析表明,在蛋白质水平上存在大量非规范 ORFs 的表达。相应的肽可能为旨在维持肌肉功能和延长健康寿命的疗法提供切入点。
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引用次数: 0
Multifunctional injectable microspheres for osteoarthritis therapy via spatiotemporally modulating macrophage polarization and inflammation 通过时空调节巨噬细胞极化和炎症,用于骨关节炎治疗的多功能注射微球
IF 7.2 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-09-17 DOI: 10.1038/s41536-024-00368-w
Shengnan Qiu, Yanbin Shi, Hengchang Zang, Xiaochen Sun, Qingjie Wang, Xianglei Fu, Hua Shen, Fanyang Mo, Yankun Zhang, Xiangqin Chen, Jiamin Zhou, Lian Li, Guimei Lin

Local injection of anti-inflammatory drugs for osteoarthritis emerged as a promising administration in the clinic, and sustained-release dosage forms have great potential for future therapeutic applications. Controlling the response of patients only in the acute inflammatory phase is currently the focus of therapeutic interventions. To relieve acute pain in patients and to improve the long-term prognosis effect of osteoarthritis treatment, we designed a two-pronged approach in this research: an injectable double-layer microsphere containing a “nonsteroidal anti-inflammatory drug - macrophage polarizing factor” was constructed. The results indicated that microspheres could regulate the intra-articular environment by inhibiting local inflammatory cytokine production, promoting macrophage polarization to the M2-phenotype, and increasing the expression of cartilage repair factors. Polymers chosen could govern the biocompatibility of microspheres and control the release sequence of the two drugs. Injection of microspheres into the degenerative articular cavity of rats leads to suppressed inflammation and well-promoted cartilage regeneration.

局部注射抗炎药物治疗骨关节炎在临床上是一种很有前景的用药方法,而缓释剂型在未来的治疗应用中具有很大的潜力。目前,仅在急性炎症阶段控制患者的反应是治疗干预的重点。为了缓解患者的急性疼痛并改善骨关节炎治疗的长期预后效果,本研究设计了一种双管齐下的方法:构建了一种含有 "非甾体抗炎药-巨噬细胞极化因子 "的可注射双层微球。结果表明,微球可以通过抑制局部炎症细胞因子的产生、促进巨噬细胞向M2表型极化以及增加软骨修复因子的表达来调节关节内环境。所选聚合物可影响微球的生物相容性,并控制两种药物的释放顺序。向大鼠退行性关节腔注射微球可抑制炎症,促进软骨再生。
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引用次数: 0
Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction Leiomodin 2 基因突变导致新生儿扩张型心肌病肌动蛋白基因特征改变和心肌细胞功能障碍
IF 7.2 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-09-16 DOI: 10.1038/s41536-024-00366-y
Jessika B. Iwanski, Christopher T. Pappas, Rachel M. Mayfield, Gerrie P. Farman, Rebecca Ahrens-Nicklas, Jared M. Churko, Carol C. Gregorio

Neonatal dilated cardiomyopathy (DCM) is a poorly understood muscular disease of the heart. Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM. Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death. Thus, it is evident that Lmod2 is essential to normal human cardiac muscle function. This study aimed to understand the underlying pathophysiology and signaling pathways related to the first reported LMOD2 variant (c.1193 G > A, p.Trp398*). Using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model harboring the homologous mutation to the patient, we discovered dysregulated actin-thin filament lengths, altered contractility and calcium handling properties, as well as alterations in the serum response factor (SRF)-dependent signaling pathway. These findings reveal that LMOD2 may be regulating SRF activity in an actin-dependent manner and provide a potential new strategy for the development of biologically active molecules to target LMOD2-related cardiomyopathies.

新生儿扩张型心肌病(DCM)是一种鲜为人知的心脏肌肉疾病。已发现编码肌动蛋白结合蛋白 Leiomodin 2 的基因 LMOD2 中的几个同卵双倍变体可导致严重的 DCM。总的来说,LMOD2 相关心肌病表现为心脏扩张和心脏收缩力下降,通常会导致新生儿死亡。由此可见,Lmod2 对人体正常心肌功能至关重要。本研究旨在了解与首次报道的 LMOD2 变异(c.1193 G > A, p.Trp398*)相关的潜在病理生理学和信号通路。利用患者特异性人类诱导多能干细胞衍生心肌细胞(hiPSC-CMs)和携带与患者同源突变的小鼠模型,我们发现了肌动蛋白细丝长度失调、收缩力和钙处理特性改变以及血清反应因子(SRF)依赖性信号通路的改变。这些发现揭示了 LMOD2 可能以肌动蛋白依赖的方式调节 SRF 的活性,并为开发针对 LMOD2 相关心肌病的生物活性分子提供了一种潜在的新策略。
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引用次数: 0
Role of umbilical cord mesenchymal stromal cells in skin rejuvenation. 脐带间充质基质细胞在皮肤年轻化中的作用。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-10 DOI: 10.1038/s41536-024-00363-1
Le Chang, Wei-Wen Fan, He-Ling Yuan, Xin Liu, Qiang Wang, Guang-Ping Ruan, Xing-Hua Pan, Xiang-Qing Zhu

Aging is the main cause of many degenerative diseases. The skin is the largest and the most intuitive organ that reflects the aging of the body. Under the interaction of endogenous and exogenous factors, there are cumulative changes in the structure, function, and appearance of the skin, which are characterized by decreased synthesis of collagen and elastin, increased wrinkles, relaxation, pigmentation, and other aging characteristics. skin aging is inevitable, but it can be delayed. The successful isolation of mesenchymal stromal cells (MSC) in 1991 has greatly promoted the progress of cell therapy in human diseases. The International Society for Cellular Therapy (ISCT) points out that the MSC is a kind of pluripotent progenitor cells that have self-renewal ability (limited) in vitro and the potential for mesenchymal cell differentiation. This review mainly introduces the role of perinatal umbilical cord-derived MSC(UC-MSC) in the field of skin rejuvenation. An in-depth and systematic understanding of the mechanism of UC-MSCs against skin aging is of great significance for the early realization of the clinical transformation of UC-MSCs. This paper summarized the characteristics of skin aging and summarized the mechanism of UC-MSCs in skin rejuvenation reported in recent years. In order to provide a reference for further research of UC-MSCs to delay skin aging.

衰老是许多退化性疾病的主要原因。皮肤是反映人体衰老的最大、最直观的器官。在内源性和外源性因素的相互作用下,皮肤的结构、功能和外观都会发生累积性变化,表现为胶原蛋白和弹性蛋白合成减少、皱纹增多、松弛、色素沉着等衰老特征。皮肤衰老是不可避免的,但可以延缓。1991 年间充质基质细胞(MSC)的成功分离极大地推动了细胞疗法在人类疾病中的应用。国际细胞治疗学会(ISCT)指出,间充质干细胞是一种具有体外自我更新能力(有限)和间充质细胞分化潜能的多能祖细胞。本综述主要介绍围产期脐带间充质干细胞(UC-MSC)在嫩肤领域的作用。深入系统地了解UC-间充质干细胞抗皮肤衰老的机制,对于早日实现UC-间充质干细胞的临床转化具有重要意义。本文总结了皮肤衰老的特点,归纳了近年来报道的UC-MSCs在皮肤年轻化中的作用机制。以期为进一步研究UC-MSCs延缓皮肤衰老提供参考。
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引用次数: 0
Exploiting in silico modelling to enhance translation of liver cell therapies from bench to bedside. 利用硅学建模促进肝细胞疗法从实验室到临床的转化。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-05-09 DOI: 10.1038/s41536-024-00361-3
Candice Ashmore-Harris, Evangelia Antonopoulou, Simon M Finney, Melissa R Vieira, Matthew G Hennessy, Andreas Muench, Wei-Yu Lu, Victoria L Gadd, Alicia J El Haj, Stuart J Forbes, Sarah L Waters

Cell therapies are emerging as promising treatments for a range of liver diseases but translational bottlenecks still remain including: securing and assessing the safe and effective delivery of cells to the disease site; ensuring successful cell engraftment and function; and preventing immunogenic responses. Here we highlight three therapies, each utilising a different cell type, at different stages in their clinical translation journey: transplantation of multipotent mesenchymal stromal/signalling cells, hepatocytes and macrophages. To overcome bottlenecks impeding clinical progression, we advocate for wider use of mechanistic in silico modelling approaches. We discuss how in silico approaches, alongside complementary experimental approaches, can enhance our understanding of the mechanisms underlying successful cell delivery and engraftment. Furthermore, such combined theoretical-experimental approaches can be exploited to develop novel therapies, address safety and efficacy challenges, bridge the gap between in vitro and in vivo model systems, and compensate for the inherent differences between animal model systems and humans. We also highlight how in silico model development can result in fewer and more targeted in vivo experiments, thereby reducing preclinical costs and experimental animal numbers and potentially accelerating translation to the clinic. The development of biologically-accurate in silico models that capture the mechanisms underpinning the behaviour of these complex systems must be reinforced by quantitative methods to assess cell survival post-transplant, and we argue that non-invasive in vivo imaging strategies should be routinely integrated into transplant studies.

细胞疗法正在成为治疗一系列肝病的有前途的方法,但转化瓶颈依然存在,包括:确保和评估将细胞安全有效地输送到疾病部位;确保细胞成功移植并发挥功能;以及防止免疫原性反应。在此,我们重点介绍三种疗法,每种疗法都利用了不同的细胞类型,并处于临床转化过程中的不同阶段:多能间充质基质/信号细胞、肝细胞和巨噬细胞的移植。为了克服阻碍临床进展的瓶颈,我们主张更广泛地使用机理硅学建模方法。我们讨论了硅学方法如何与补充实验方法一起,加深我们对细胞成功输送和移植机制的理解。此外,这种理论与实验相结合的方法可用于开发新型疗法、解决安全性和有效性难题、弥合体外和体内模型系统之间的差距,以及弥补动物模型系统与人类之间的固有差异。我们还重点介绍了硅学模型开发如何能够减少体内实验次数,提高实验针对性,从而降低临床前成本和实验动物数量,并加快向临床转化的速度。我们认为,非侵入性体内成像策略应常规纳入移植研究。
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引用次数: 0
Structural, angiogenic, and immune responses influencing myocardial regeneration: a glimpse into the crucible 影响心肌再生的结构、血管生成和免疫反应:熔炉一瞥
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-30 DOI: 10.1038/s41536-024-00357-z
Basil M. Baccouche, Stefan Elde, Hanjay Wang, Y. Joseph Woo

Complete cardiac regeneration remains an elusive therapeutic goal. Although much attention has been focused on cardiomyocyte proliferation, especially in neonatal mammals, recent investigations have unearthed mechanisms by which non-cardiomyocytes, such as endothelial cells, fibroblasts, macrophages, and other immune cells, play critical roles in modulating the regenerative capacity of the injured heart. The degree to which each of these cell types influence cardiac regeneration, however, remains incompletely understood. This review highlights the roles of these non-cardiomyocytes and their respective contributions to cardiac regeneration, with emphasis on natural heart regeneration after cardiac injury during the neonatal period.

完全的心脏再生仍然是一个难以实现的治疗目标。尽管心肌细胞增殖(尤其是新生哺乳动物的心肌细胞增殖)一直备受关注,但最近的研究发现了非心肌细胞(如内皮细胞、成纤维细胞、巨噬细胞和其他免疫细胞)在调节损伤心脏再生能力方面发挥关键作用的机制。然而,人们对这些细胞类型对心脏再生的影响程度仍不甚了解。本综述将重点介绍这些非心肌细胞的作用及其各自对心脏再生的贡献,重点是新生儿期心脏损伤后的自然心脏再生。
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引用次数: 0
Epigenetic mechanisms regulate sex differences in cardiac reparative functions of bone marrow progenitor cells 表观遗传机制调控骨髓祖细胞心脏修复功能的性别差异
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-29 DOI: 10.1038/s41536-024-00362-2
Charan Thej, Rajika Roy, Zhongjian Cheng, Venkata Naga Srikanth Garikipati, May M. Truongcao, Darukeshwara Joladarashi, Vandana Mallaredy, Maria Cimini, Carolina Gonzalez, Ajit Magadum, Jayashri Ghosh, Cindy Benedict, Walter J. Koch, Raj Kishore

Historically, a lower incidence of cardiovascular diseases (CVD) and related deaths in women as compared with men of the same age has been attributed to female sex hormones, particularly estrogen and its receptors. Autologous bone marrow stem cell (BMSC) clinical trials for cardiac cell therapy overwhelmingly included male patients. However, meta-analysis data from these trials suggest a better functional outcome in postmenopausal women as compared with aged-matched men. Mechanisms governing sex-specific cardiac reparative activity in BMSCs, with and without the influence of sex hormones, remain unexplored. To discover these mechanisms, Male (M), female (F), and ovariectomized female (OVX) mice-derived EPCs were subjected to a series of molecular and epigenetic analyses followed by in vivo functional assessments of cardiac repair. F-EPCs and OVX EPCs show a lower inflammatory profile and promote enhanced cardiac reparative activity after intra-cardiac injections in a male mouse model of myocardial infarction (MI). Epigenetic sequencing revealed a marked difference in the occupancy of the gene repressive H3K9me3 mark, particularly at transcription start sites of key angiogenic and proinflammatory genes in M-EPCs compared with F-EPCs and OVX-EPCs. Our study unveiled that functional sex differences in EPCs are, in part, mediated by differential epigenetic regulation of the proinflammatory and anti-angiogenic gene CCL3, orchestrated by the control of H3K9me3 by histone methyltransferase, G9a/Ehmt2. Our research highlights the importance of considering the sex of donor cells for progenitor-based tissue repair.

从历史上看,与同龄男性相比,女性心血管疾病(CVD)发病率和相关死亡率较低,这归因于女性性激素,尤其是雌激素及其受体。用于心脏细胞治疗的自体骨髓干细胞(BMSC)临床试验绝大多数包括男性患者。然而,这些试验的荟萃分析数据表明,与年龄匹配的男性相比,绝经后女性的功能结果更好。BMSCs 的心脏修复活动具有性别特异性,无论是否受性激素影响,其作用机制仍有待探索。为了发现这些机制,我们对雄性(M)、雌性(F)和卵巢切除的雌性(OVX)小鼠来源的EPC进行了一系列分子和表观遗传学分析,然后进行了体内心脏修复功能评估。在雄性小鼠心肌梗死(MI)模型中,F-EPCs和OVX EPCs在心内注射后显示出较低的炎症特征,并促进了心脏修复活动。表观遗传测序显示,与F-EPCs和OVX-EPCs相比,M-EPCs在基因抑制性H3K9me3标记的占有率上存在明显差异,尤其是在关键血管生成基因和促炎基因的转录起始位点。我们的研究揭示了 EPCs 的功能性性别差异部分是由促炎和抗血管生成基因 CCL3 的不同表观遗传调控介导的,而这种调控是由组蛋白甲基转移酶 G9a/Ehmt2 对 H3K9me3 的控制协调的。我们的研究强调了考虑供体细胞性别对基于祖细胞的组织修复的重要性。
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引用次数: 0
The adult environment promotes the transcriptional maturation of human iPSC-derived muscle grafts 成人环境促进人类 iPSC 衍生肌肉移植物的转录成熟
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-04 DOI: 10.1038/s41536-024-00360-4
Sarah B. Crist, Karim Azzag, James Kiley, Ilsa Coleman, Alessandro Magli, Rita C. R. Perlingeiro

Pluripotent stem cell (PSC)-based cell therapy is an attractive option for the treatment of multiple human disorders, including muscular dystrophies. While in vitro differentiating PSCs can generate large numbers of human lineage-specific tissue, multiple studies evidenced that these cell populations mostly display embryonic/fetal features. We previously demonstrated that transplantation of PSC-derived myogenic progenitors provides long-term engraftment and functional improvement in several dystrophic mouse models, but it remained unknown whether donor-derived myofibers mature to match adult tissue. Here, we transplanted iPAX7 myogenic progenitors into muscles of non-dystrophic and dystrophic mice and compared the transcriptional landscape of human grafts with respective in vitro-differentiated iPAX7 myotubes as well as human skeletal muscle biospecimens. Pairing bulk RNA sequencing with computational deconvolution of human reads, we were able to pinpoint key myogenic changes that occur during the in vitro–to–in vivo transition, confirm developmental maturity, and consequently evaluate their applicability for cell-based therapies.

以多能干细胞(PSC)为基础的细胞疗法是治疗包括肌肉萎缩症在内的多种人类疾病的一种极具吸引力的选择。虽然体外分化的多能干细胞能产生大量的人系特异性组织,但多项研究证明,这些细胞群大多显示出胚胎/胎儿特征。我们以前曾证实,移植来源于造血干细胞的肌原祖细胞可在几种肌营养不良小鼠模型中提供长期的移植和功能改善,但供体来源的肌纤维是否成熟到与成人组织相匹配仍是未知数。在这里,我们将 iPAX7 肌原细胞移植到非肌营养不良小鼠和肌营养不良小鼠的肌肉中,并比较了人类移植物与各自体外分化的 iPAX7 肌管以及人类骨骼肌生物样本的转录情况。通过将大量 RNA 测序与人类读数的计算解卷积配对,我们能够确定体外到体内转变过程中发生的关键肌生成变化,确认发育成熟度,从而评估它们对细胞疗法的适用性。
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引用次数: 0
A two-way street – cellular metabolism and myofibroblast contraction 双行道--细胞新陈代谢与肌成纤维细胞收缩
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-03 DOI: 10.1038/s41536-024-00359-x
Anne Noom, Birgit Sawitzki, Petra Knaus, Georg N. Duda

Tissue fibrosis is characterised by the high-energy consumption associated with myofibroblast contraction. Although myofibroblast contraction relies on ATP production, the role of cellular metabolism in myofibroblast contraction has not yet been elucidated. Studies have so far only focused on myofibroblast contraction regulators, such as integrin receptors, TGF-β and their shared transcription factor YAP/TAZ, in a fibroblast-myofibroblast transition setting. Additionally, the influence of the regulators on metabolism and vice versa have been described in this context. However, this has so far not yet been connected to myofibroblast contraction. This review focuses on the known and unknown of how cellular metabolism influences the processes leading to myofibroblast contraction and vice versa. We elucidate the signalling cascades responsible for myofibroblast contraction by looking at FMT regulators, mechanical cues, biochemical signalling, ECM properties and how they can influence and be influenced by cellular metabolism. By reviewing the existing knowledge on the link between cellular metabolism and the regulation of myofibroblast contraction, we aim to pinpoint gaps of knowledge and eventually help identify potential research targets to identify strategies that would allow switching tissue fibrosis towards tissue regeneration.

组织纤维化的特点是与肌成纤维细胞收缩相关的高能量消耗。虽然肌成纤维细胞的收缩依赖于 ATP 的产生,但细胞代谢在肌成纤维细胞收缩中的作用尚未阐明。迄今为止,研究仅关注成纤维细胞-肌成纤维细胞转化环境中的肌成纤维细胞收缩调节因子,如整合素受体、TGF-β 及其共有转录因子 YAP/TAZ。此外,在这种情况下,还描述了调节因子对新陈代谢的影响,以及反之亦然。然而,迄今为止还没有将其与肌成纤维细胞收缩联系起来。本综述将重点讨论细胞新陈代谢如何影响肌成纤维细胞收缩过程以及反之亦然的已知和未知因素。我们通过研究 FMT 调节因子、机械线索、生化信号、ECM 特性以及它们如何影响细胞新陈代谢以及如何被细胞新陈代谢影响,来阐明负责肌成纤维细胞收缩的信号级联。通过回顾有关细胞代谢与肌成纤维细胞收缩调控之间联系的现有知识,我们旨在找出知识差距,并最终帮助确定潜在的研究目标,从而确定可将组织纤维化转变为组织再生的策略。
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引用次数: 0
Comparison studies identify mesenchymal stromal cells with potent regenerative activity in osteoarthritis treatment. 对比研究发现间充质基质细胞在骨关节炎治疗中具有强大的再生活性。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2024-04-01 DOI: 10.1038/s41536-024-00358-y
Hongshang Chu, Shaoyang Zhang, Zhenlin Zhang, Hua Yue, Huijuan Liu, Baojie Li, Feng Yin

Osteoarthritis affects 15% of people over 65 years of age. It is characterized by articular cartilage degradation and inflammation, leading to joint pain and disability. Osteoarthritis is incurable and the patients may eventually need joint replacement. An emerging treatment is mesenchymal stromal cells (MSCs), with over two hundred clinical trials being registered. However, the outcomes of these trials have fallen short of the expectation, due to heterogeneity of MSCs and uncertain mechanisms of action. It is generally believed that MSCs exert their function mainly by secreting immunomodulatory and trophic factors. Here we used knee osteoarthritis mouse model to assess the therapeutic effects of MSCs isolated from the white adipose or dermal adipose tissue of Prrx1-Cre; R26tdTomato mice and Dermo1-Cre; R26tdTomato mice. We found that the Prrx1-lineage MSCs from the white adipose tissues showed the greatest in vitro differentiation potentials among the four MSC groups and single cell profiling showed that the Prrx1-lineage MSCs contained more stem cells than the Dermo1 counterpart. Only the Prrx1-lineage cells isolated from white adipose tissues showed long-term therapeutic effectiveness on early-stage osteoarthritis models. Mechanistically, Prrx1-lineage MSCs differentiated into Col2+ chondrocytes and replaced the damage cartilage, activated Col1 expressing in resident chondrocytes, and inhibited synovial inflammation. Transcriptome analysis showed that the articular chondrocytes derived from injected MSCs expressed immunomodulatory cytokines, trophic factors, and chondrocyte-specific genes. Our study identified a MSC population genetically marked by Prrx1 that has great multipotentiality and can differentiate into chondrocytes to replace the damaged cartilage.

在 65 岁以上的人群中,15% 的人患有骨关节炎。其特点是关节软骨退化和炎症,导致关节疼痛和残疾。骨关节炎无法治愈,患者最终可能需要进行关节置换。间充质干细胞(MSCs)是一种新兴的治疗方法,目前已有两百多项临床试验登记在册。然而,由于间充质干细胞的异质性和作用机制的不确定性,这些试验的结果并不尽如人意。一般认为,间充质干细胞主要通过分泌免疫调节因子和营养因子来发挥其功能。在此,我们利用膝骨关节炎小鼠模型评估了从Prrx1-Cre; R26tdTomato小鼠和Dermo1-Cre; R26tdTomato小鼠的白色脂肪组织或真皮脂肪组织中分离的间充质干细胞的治疗效果。我们发现,在四组间充质干细胞中,来自白色脂肪组织的Prrx1系间充质干细胞显示出最大的体外分化潜能,单细胞分析表明,Prrx1系间充质干细胞比Dermo1系间充质干细胞含有更多的干细胞。只有从白脂肪组织中分离出的Prrx1系细胞对早期骨关节炎模型有长期治疗效果。从机理上讲,Prrx1系间叶干细胞分化为Col2+软骨细胞,取代了受损软骨,激活了常住软骨细胞中Col1的表达,并抑制了滑膜炎症。转录组分析表明,注入间充质干细胞的关节软骨细胞表达免疫调节细胞因子、营养因子和软骨细胞特异性基因。我们的研究发现了一种以 Prrx1 为基因标记的间充质干细胞群体,它具有很强的多潜能性,可以分化成软骨细胞来替代受损软骨。
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