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Cleft Palate Induced by Augmented Fibroblast Growth Factor-9 Signaling in Cranial Neural Crest Cells in Mice. 小鼠颅神经嵴细胞中成纤维细胞生长因子-9信号增强诱发腭裂。
Pub Date : 2024-10-01 Epub Date: 2024-08-22 DOI: 10.1089/scd.2024.0077
Chensheng Lin, Shiyu Liu, Ningsheng Ruan, Jiang Chen, YiPing Chen, Yanding Zhang, Jian Zhang

Although enhanced fibroblast growth factor (FGF) signaling has been demonstrated to be crucial in many cases of syndromic cleft palate caused by tongue malposition in humans, animal models that recapitulate this phenotype are limited, and the precise mechanisms remain elusive. Mutations in FGF9 with the effect of either loss- or gain-of-function effects have been identified to be associated with cleft palate in humans. Here, we generated a mouse model with a transgenic Fgf9 allele specifically activated in cranial neural crest cells, aiming to elucidate the gain-of-function effects of Fgf9 in palatogenesis. We observed cleft palate with 100% penetrance in mutant mice. Further analysis demonstrated that no inherent defects in the morphogenic competence of palatal shelves could be found, but a passively lifted tongue prevented the elevation of palatal shelves, leading to the cleft palate. This tongue malposition was induced by posterior spatial confinement that was exerted by temporomandibular joint (TMJ) dysplasia characterized by a reduction in Sox9+ progenitors within the condyle and a structural decrease in the posterior dimension of the lower jaw. Our findings highlight the critical role of excessive FGF signaling in disrupting spatial coordination during palate development and suggest a potential association between palatal shelf elevation and early TMJ development.

尽管成纤维细胞生长因子(FGF)信号传导增强已被证实在许多由人类舌位不正引起的综合征腭裂病例中起着关键作用,但能再现这种表型的动物模型却很有限,其确切的机制仍难以捉摸。已发现 FGF9 基因突变具有功能缺失或功能增益效应,与人类腭裂有关。在这里,我们用特异性激活颅神经嵴细胞(CNCCs)的转基因 Fgf9 等位基因生成了一个小鼠模型,旨在阐明 Fgf9 在腭裂发生过程中的功能增益效应。我们观察到突变小鼠腭裂的穿透率为 100%。进一步的分析表明,腭骨架的形态发生能力没有固有缺陷,但被动抬高的舌头阻碍了腭骨架的抬高,导致了腭裂。这种舌错位是由颞下颌关节(TMJ)发育不良造成的后部空间限制诱发的,其特点是髁突内Sox9+祖细胞减少和下颌骨后部结构性尺寸减小。我们的研究结果突显了过多的 FGF 信号在破坏腭发育过程中的空间协调性中的关键作用,并表明腭骨架抬高与早期颞下颌关节发育之间存在潜在联系。
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引用次数: 0
Differentiation, Metabolism, and Cardioprotective Secretory Functions of Human Cardiac Stromal Cells from Ischemic and Endocarditis Patients. 来自缺血和心内膜炎患者的人类心脏基质细胞的分化、代谢和心脏保护分泌功能。
Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI: 10.1089/scd.2024.0103
Helen Nguyen, Chuan-Chih Hsu, Annette Meeson, Rachel Oldershaw, Gavin Richardson, Andreas Czosseck, David J Lundy

This study investigates the characteristics of cardiac mesenchymal stem cell-like cells (CMSCLCs) isolated from the right atrial appendage of human donors with ischemia and a young patient with endocarditis (NE-CMSCLCs). Typical CMSCLCs from ischemic heart patients were derived from coronary artery bypass grafting procedures and compared against bone marrow mesenchymal stromal cells (BM-MSCs). NE-CMSCLCs had a normal immunophenotype, but exhibited enhanced osteogenic differentiation potential, rapid proliferation, reduced senescence, reduced glycolysis, and lower reactive oxygen species generation after oxidative stress compared with typical ischemic CMSCLCs. These differences suggest a unique functional status of NE-CMSCLCs, influenced by the donor health condition. Despite large variances in their paracrine secretome, NE-CMSCLCs retained therapeutic potential, as indicated by their ability to protect hypoxia/reoxygenation-injured human cardiomyocytes, albeit less effectively than typical CMSCLCs. This research describes a unique cell phenotype and underscores the importance of donor health status in the therapeutic efficacy of autologous cardiac cell therapy.

本研究调查了从缺血的人体捐献者和一名年轻的心内膜炎患者的右心房阑尾分离出来的心脏间充质干细胞样细胞(CMSCLCs)(NE-CMSCLCs)的特征。缺血性心脏病患者的典型 CMSCLCs 来自冠状动脉旁路移植手术,并与骨髓间充质基质细胞(BM-MSCs)进行了比较。NE-CMSCLCs具有正常的免疫表型,但与典型的缺血性CMSCLCs相比,NE-CMSCLCs具有更强的成骨分化潜能、快速增殖、减少衰老、减少糖酵解以及在氧化应激后产生更少的活性氧。这些差异表明,受供体健康状况的影响,NE-CMSCLCs 具有独特的功能状态。尽管它们的旁分泌组存在很大差异,但NE-CMSCLCs仍具有治疗潜力,这体现在它们能够保护缺氧/复氧损伤的人类心肌细胞,尽管效果不如典型的CMSCLCs。这项研究描述了一种独特的细胞表型,并强调了供体健康状况对自体心脏细胞疗法疗效的重要性。
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引用次数: 0
Stem Cell Division and Its Critical Role in Mammary Gland Development and Tumorigenesis: Current Progress and Remaining Challenges. 干细胞分裂及其在乳腺发育和肿瘤发生中的关键作用:当前的进展和依然存在的挑战。
Pub Date : 2024-09-01 Epub Date: 2024-08-07 DOI: 10.1089/scd.2024.0035
Peng Zeng, Lin-Zhen Shu, Yu-Hong Zhou, Hai-Lin Huang, Shu-Hua Wei, Wen-Jian Liu, Huan Deng

The origin of breast cancer (BC) has traditionally been a focus of medical research. It is widely acknowledged that BC originates from immortal mammary stem cells and that these stem cells participate in two division modes: symmetric cell division (SCD) and asymmetrical cell division (ACD). Although both of these modes are key to the process of breast development and their imbalance is closely associated with the onset of BC, the molecular mechanisms underlying these phenomena deserve in-depth exploration. In this review, we first outline the molecular mechanisms governing ACD/SCD and analyze the role of ACD/SCD in various stages of breast development. We describe that the changes in telomerase activity, the role of polar proteins, and the stimulation of ovarian hormones subsequently lead to two distinct consequences: breast development or carcinogenesis. Finally, gene mutations, abnormalities in polar proteins, modulation of signal-transduction pathways, and alterations in the microenvironment disrupt the balance of BC stem cell division modes and cause BC. Important regulatory factors such as mammalian Inscuteable mInsc, Numb, Eya1, PKCα, PKCθ, p53, and IL-6 also play significant roles in regulating pathways of ACD/SCD and may constitute key targets for future research on stem cell division, breast development, and tumor therapy.

乳腺癌(BC)的起源历来是医学研究的重点。人们普遍认为,乳腺癌起源于永生的乳腺干细胞(MaSCs),这些干细胞参与两种分裂模式:对称细胞分裂(SCD)和非对称细胞分裂(ACD)。虽然这两种模式都是乳腺发育过程中的关键,而且它们的失衡与乳腺癌的发病密切相关,但这些现象背后的分子机制值得深入探讨。在这篇综述中,我们首先概述了ACD/SCD的分子机制,并分析了ACD/SCD在乳腺发育各个阶段的作用。我们描述了端粒酶活性的变化、极性蛋白的作用以及卵巢激素的刺激随后会导致两种不同的后果:乳腺发育或癌变。最后,基因突变、极性蛋白的异常、信号转导通路的调节以及微环境的改变会破坏乳腺癌干细胞(BCSCs)分裂模式的平衡,导致乳腺癌。重要的调控因子,如哺乳动物可抑制分裂因子(mInsc)、Numb、Eya1、PKCα、PKCθ、p53和IL-6等,也在ACD/SCD的调控途径中发挥重要作用,可能成为未来干细胞分裂、乳腺发育和肿瘤治疗研究的关键靶点。
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引用次数: 0
Vitamin D3 Improves Adipose Stromal Cell Survival and Human Fat Graft Retention in Xenograft Model. 维生素 D3 提高异种移植模型中脂肪基质细胞的存活率和人类脂肪移植的保留率
Pub Date : 2024-09-01 Epub Date: 2024-07-24 DOI: 10.1089/scd.2024.0056
Andreea Gavrilescu, Shawn J Loder, Rachel Ricketts, Phoebe Lee, Divya Ramkumar, Bahaa Shaaban, Amr Elmeanawy, Alexandra Vagonis, Jeffrey A Gusenoff, J Peter Rubin, Lauren E Kokai

Adipose stem cells are considered one of the primary drivers of autologous fat graft biological activity and survival. We have previously demonstrated that hormonally active VD3 improved adipose stem cell viability in ex vivo and in vivo fat grafting models. In this study, we evaluated the inactive form of VD3 (cholecalciferol) on adipose stromal cell (ASC) phenotype during hypoxia and the subsequent effect on human fat graft retention in the xenograft model. Lipoaspirate collected from six human donors was used for ex vivo particle culture studies and isolated ASC studies. Adipose particles were treated with increasing doses of VD3 to determine impact on ASC survival. Expanded stromal cells were treated with VD3 during hypoxic culture and assessed for viability, apoptosis, mitochondrial activity, and nitric oxide (NO) release via caspase, DAF-FM, or TMRM. Finally, 40 Nu/J mice receiving bilateral dorsal human lipoaspirate were treated thrice weekly with (1) vehicle control, (2) 50 ng calcitriol, (3) 50 ng VD3, (4) 500 ng VD3, and (5) 5,000 ng VD3 for 12 weeks, n = 8 per group. Graft weight, volume, and architecture were analyzed. Adipose particles treated with dose-escalating VD3 had significantly increased ASC viability compared with control (P < 0.01). Under hypoxia, ASCs treated with 1 nM VD3 had significantly greater viability than untreated and pretreated cells (P < 0.01, P < 0.01) and significantly lower apoptosis-to-viability ratio (P < 0.01). ASCs pretreated with 1 nM VD3 had significantly lower NO release (P < 0.05) and lower mitochondrial polarization (P < 0.05) compared with controls. In vivo results showed mice receiving 5,000 ng VD3 had significantly greater graft weight (P < 0.05) and volume (P < 0.05) after 12 weeks of treatment compared with controls. Grafts had enhanced neovascularization, intact adipocyte architecture, and absence of oil cysts. VD3 is an over-the-counter nutritional supplement with a known safety profile in humans. Our xenograft model suggests administering VD3 at the time of surgery may significantly improve fat graft retention.

脂肪干细胞被认为是自体脂肪移植生物活性和存活率的主要驱动力之一。我们之前已经证明,在体内外脂肪移植模型中,具有激素活性的VD3能提高脂肪干细胞的存活率。在这项研究中,我们评估了非活性形式的 VD3(胆钙化醇)在缺氧过程中对脂肪基质细胞表型的影响,以及随后对异种移植模型中人类脂肪移植保留的影响。从六名人体捐献者身上采集的脂肪汲取物被用于体内外颗粒培养研究和分离 ASC 研究。用增加剂量的 VD3 处理脂肪颗粒,以确定其对 ASC 存活率的影响。在缺氧培养过程中,用 VD3 处理扩大的基质细胞,并通过 Caspase、DAF-FM 或 TMRM 评估其存活率、凋亡、线粒体活性和一氧化氮释放情况。最后,40 只接受双侧人体背侧吸脂的 Nu/J 小鼠每周三次接受 1) 车辆对照、2) 50ng 降钙三醇、3) 50ng VD3、4) 500ng VD3 和 5) 5000ng VD3 治疗,为期 12 周,每组 8 只。对移植物的重量、体积和结构进行分析。与对照组相比,经剂量递增的 VD3 处理的脂肪颗粒的 ASC 存活率显著增加(p
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引用次数: 0
Prostaglandin E2 Induces YAP1 and Agrin Through EP4 in Neonatally-Derived Islet-1+ Stem Cells. 前列腺素 E2 通过 EP4 在新生儿胰岛-1+干细胞中诱导 YAP1 和 Agrin。
Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI: 10.1089/scd.2024.0069
Lorelei Hughes, Larry V Lopez, Mary Kearns-Jonker

Prostaglandin E2 (PGE2) has recently gained attention in the field of regenerative medicine because of the beneficial effects of this molecule on stem cell proliferation and migration. Furthermore, PGE2 has the ability to mitigate immune rejection and fibrosis. In the colon and kidney, PGE2 induces YAP1, a transcription factor critical for cardiac regeneration. Establishing a similar connection in stem cells that can be transplanted in the heart could lead to the development of more effective therapeutics. In this report, we identify the effects of PGE2 on neonatal Islet-1+ stem cells. These stem cells synthesize PGE2, which functions by stimulating the transcription of the extracellular matrix protein Agrin. Agrin upregulates YAP1. Consequently, both YAP1 and Agrin are induced by PGE2 treatment. Our study shows that PGE2 upregulated the expression of both YAP1 and Agrin in Islet-1+ stem cells through the EP4 receptor and stimulated proliferation using the same mechanisms. PGE2 administration further elevated the expression of stemness markers and the matrix metalloproteinase MMP9, a key regulator of remodeling in the extracellular matrix post-injury. The expression of PGE2 in neonatal Islet-1+ cells is a factor which contributes to improving the functional efficacy of these cells for cardiac repair.

前列腺素E2(PGE2)最近在再生医学领域备受关注,因为这种分子对干细胞的增殖和迁移有好处。此外,PGE2还能减轻免疫排斥和纤维化。在结肠和肾脏中,PGE2能诱导YAP1,这是一种对心脏再生至关重要的转录因子。在可移植到心脏的干细胞中建立类似的联系,可开发出更有效的疗法。在本报告中,我们确定了PGE2对新生儿胰岛-1+干细胞的影响。这些干细胞合成PGE2,PGE2通过刺激细胞外基质蛋白Agrin的转录发挥作用。Agrin能上调YAP1。因此,PGE2 会诱导 YAP1 和 Agrin。我们的研究表明,PGE2 通过 EP4 受体上调胰岛-1+干细胞中 YAP1 和 Agrin 的表达,并通过相同的机制刺激细胞增殖。PGE2进一步提高了干性标志物和基质金属蛋白酶MMP9的表达,MMP9是损伤后细胞外基质重塑的关键调节因子。PGE2在新生儿胰岛-1+细胞中的表达有助于提高这些细胞在心脏修复中的功能效率。
{"title":"Prostaglandin E2 Induces YAP1 and Agrin Through EP4 in Neonatally-Derived Islet-1+ Stem Cells.","authors":"Lorelei Hughes, Larry V Lopez, Mary Kearns-Jonker","doi":"10.1089/scd.2024.0069","DOIUrl":"10.1089/scd.2024.0069","url":null,"abstract":"<p><p>Prostaglandin E2 (PGE2) has recently gained attention in the field of regenerative medicine because of the beneficial effects of this molecule on stem cell proliferation and migration. Furthermore, PGE2 has the ability to mitigate immune rejection and fibrosis. In the colon and kidney, PGE2 induces YAP1, a transcription factor critical for cardiac regeneration. Establishing a similar connection in stem cells that can be transplanted in the heart could lead to the development of more effective therapeutics. In this report, we identify the effects of PGE2 on neonatal Islet-1+ stem cells. These stem cells synthesize PGE2, which functions by stimulating the transcription of the extracellular matrix protein Agrin. Agrin upregulates YAP1. Consequently, both YAP1 and Agrin are induced by PGE2 treatment. Our study shows that PGE2 upregulated the expression of both <i>YAP1</i> and <i>Agrin</i> in Islet-1+ stem cells through the EP4 receptor and stimulated proliferation using the same mechanisms. PGE2 administration further elevated the expression of stemness markers and the matrix metalloproteinase <i>MMP9</i>, a key regulator of remodeling in the extracellular matrix post-injury. The expression of PGE2 in neonatal Islet-1+ cells is a factor which contributes to improving the functional efficacy of these cells for cardiac repair.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"496-504"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Direct Water-Soluble Molecules Transfer from Transplanted Bone Marrow Mononuclear Cell to Hippocampal Neural Stem Cells. 从移植的骨髓单核细胞向海马神经干细胞直接转移水溶性分子。
Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI: 10.1089/scd.2024.0043
Yuka Okinaka, Mitsuyo Maeda, Yosky Kataoka, Takayuki Nakagomi, Akiko Doi, Johannes Boltze, Carsten Claussen, Sheraz Gul, Akihiko Taguchi

Intravascularly transplanted bone marrow cells, including bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells, transfer water-soluble molecules to cerebral endothelial cells via gap junctions. After transplantation of BM-MNC, this fosters hippocampal neurogenesis and enhancement of neuronal function. Herein, we report the impact of transplanted BM-MNC on neural stem cells (NSC) in the brain. Surprisingly, direct transfer of water-soluble molecules from transplanted BM-MNC and peripheral mononuclear cells to NSC in the hippocampus was observed already 10 min after cell transplantation, and transfer from BM-MNC to GFAP-positive cortical astrocytes was also observed. In vitro investigations revealed that BM-MNC abolish the expression of hypoxia-inducible factor-1α in astrocytes. We suggest that the transient and direct transfer of water-soluble molecules between cells in circulation and NSC in the brain may be one of the biological mechanisms underlying the repair of brain function.

血管内移植的骨髓细胞,包括骨髓单核细胞(BM-MNC)和间充质干细胞,可通过间隙连接将水溶性分子转移到大脑内皮细胞。BM-MNC 移植后,可促进海马神经发生,增强神经元功能。在此,我们报告了移植的 BM-MNC 对大脑神经干细胞(NSC)的影响。令人惊讶的是,在细胞移植后10分钟,就观察到水溶性分子从移植的BM-MNC和外周单核细胞直接转移到海马的神经干细胞,还观察到BM-MNC转移到GFAP阳性的皮层星形胶质细胞。体外研究显示,BM-MNC 可抑制 HIF1α 在星形胶质细胞中的表达。我们认为,水溶性分子在循环中的细胞和大脑中的 NSC 之间的短暂直接转移可能是大脑功能修复的生物机制之一。
{"title":"Direct Water-Soluble Molecules Transfer from Transplanted Bone Marrow Mononuclear Cell to Hippocampal Neural Stem Cells.","authors":"Yuka Okinaka, Mitsuyo Maeda, Yosky Kataoka, Takayuki Nakagomi, Akiko Doi, Johannes Boltze, Carsten Claussen, Sheraz Gul, Akihiko Taguchi","doi":"10.1089/scd.2024.0043","DOIUrl":"10.1089/scd.2024.0043","url":null,"abstract":"<p><p>Intravascularly transplanted bone marrow cells, including bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells, transfer water-soluble molecules to cerebral endothelial cells via gap junctions. After transplantation of BM-MNC, this fosters hippocampal neurogenesis and enhancement of neuronal function. Herein, we report the impact of transplanted BM-MNC on neural stem cells (NSC) in the brain. Surprisingly, direct transfer of water-soluble molecules from transplanted BM-MNC and peripheral mononuclear cells to NSC in the hippocampus was observed already 10 min after cell transplantation, and transfer from BM-MNC to GFAP-positive cortical astrocytes was also observed. In vitro investigations revealed that BM-MNC abolish the expression of hypoxia-inducible factor-1α in astrocytes. We suggest that the transient and direct transfer of water-soluble molecules between cells in circulation and NSC in the brain may be one of the biological mechanisms underlying the repair of brain function.</p>","PeriodicalId":94214,"journal":{"name":"Stem cells and development","volume":" ","pages":"505-515"},"PeriodicalIF":0.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141725428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Differential Secretomes of Processed Adipose Grafts, the Stromal Vascular Fraction, and Adipose-Derived Stem Cells. 加工过的脂肪移植物、基质血管馏分和脂肪来源干细胞的不同分泌物。
Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI: 10.1089/scd.2024.0071
Hannah Carr, Malke Asaad, Yewen Wu, Cynthia Branch-Brooks, Qixu Zhang, Peiman Hematti, Summer E Hanson

There are multiple methods to prepare lipoaspirate for autologous fat transfer; however, graft retention remains unpredictable. The purpose of this study was to compare the cellular and protein composition of adipose grafts and the stromal vascular fraction (SVF) resulting from three common techniques to prepare adipose grafts. Adipose grafts were harvested from healthy donors and processed via three techniques: centrifugation (C), a single-filter (SF) device, and a double-filtration (DF) system. Part of each graft was analyzed or further processed to isolate the SVF. Cell viability, surface markers, cytokine, and growth factors were compared between the graft and SVF as well as adipose-derived stem cells (ASCs). Overall, we found variations across the three processing techniques and among the graft components (ASCs, SVF, and fat). Cell viability within the grafts was similar (94.6%, 92.3%, and 93.6%; P = 0.93). The trend was a greater percentage of ASCs from SF versus DF or centrifugation (6.95%, 4.63%, and 1.93%, respectively, P = 0.06). Adipogenic markers (adiponectin and leptin) were similar among all three grafts (P = 0.45). Markers of tissue remodeling were greatest in the SVF compared with fat and ASCs, regardless of processing technique. There was higher relative expression of MMP-9 (2×), Extracellular matrix metalloproteinase inducer (EMMPRIN) (2.5×), endoglin (5×), and IL-8 (1.5×) in the SVF (P < 0.005). Our study identified differences in cytokine expression in adipose grafts and the SVF, particularly in cytokines important in inflammation and wound healing. These secretomes may impact graft retention and fat necrosis and have the potential implications in cell-assisted lipotransfer. There were no significant differences between the final products of any of the processing techniques.

有多种方法可以制备用于自体脂肪移植的脂肪抽吸物,但移植体的保留仍然难以预测。本研究的目的是比较脂肪移植物和基质血管部分(SVF)的细胞和蛋白质组成,这些组成来自三种常用的脂肪移植物制备技术。脂肪移植物取自健康供体,并通过三种技术进行处理:离心(C)、单层过滤(SF)装置和双层过滤(DF)系统。对每个移植物的一部分进行分析或进一步处理,以分离 SVF。我们比较了移植物和 SVF 以及脂肪衍生干细胞(ASCs)的细胞活力、表面标志物、细胞因子和生长因子。总体而言,我们发现三种处理技术和移植物成分(ASCs、SVF、脂肪)之间存在差异。移植物内的细胞存活率相似(94.6%、92.3%和93.6%;P=0.93)。趋势是 SF 与 DF 或离心分离的 ASCs 百分比更高(分别为 6.95%、4.63% 和 1.93%;P=0.06)。三种移植物的成脂标志物(脂肪连素、瘦素)相似(P=0.45)。与脂肪和 ASCs 相比,无论加工技术如何,SVF 中的组织重塑标志物最多。在 SVF 中,MMP9(2 倍)、EMMPRIN(2.5 倍)、endoglin(5 倍)和 IL-8 (1.5 倍)的相对表达量更高(p=0.45)。
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引用次数: 0
Overexpression of NDNF Improves the Cytoprotective Effects of Aged Human Bone Marrow Mesenchymal Stem Cells by Modulating Oxidative Stress and Apoptosis. 过表达 NDNF 可通过调节氧化应激和细胞凋亡改善老化人骨髓间充质干细胞的细胞保护作用。
Pub Date : 2024-08-01 Epub Date: 2024-06-26 DOI: 10.1089/scd.2023.0289
Yang Liu, Juan Ren, Ruidan Bai, Sheng He, Zexu Peng, Wenjuan Yin, Rui Guo, Jianqiang Niu, Weiguo Zhang, Zhongnian Xia, Xuemei Fan, Kun Yang, Bin Li, Hailan Yang, Huifang Song, Jun Xie

The therapeutic potential of autologous stem cell transplantation for heart repair diminishes in the elderly due to stem cell aging. Rejuvenating aged stem cells to enhance their protective effects on injured cardiomyocytes is crucial for aging patients with heart failure. In this study, we aimed to investigate whether neuron-derived neurotrophic factor (NDNF) over-expression improves the protective effect of aged stem cells for injured cardiomyocytes and explore the underlying mechanism. Human bone marrow was collected from both young and old patients, and bone marrow mesenchymal stem cells (BMSCs) were cultured. Lentivirus expression vectors carrying NDNF genes were used to transfect aged BMSCs. Fatal hypoxia-induced injury in H9C2 cells served as an in vitro ischemia model. The conditioned medium from different BMSC groups was applied to assess the beneficial effects on hypoxia-induced damage in myocardial H9C2 cells. Results revealed that the conditioned medium of NDNF over-expressed old BMSCs increased H9C2 cell viability and reduced oxidative stress and apoptosis levels under fatal hypoxia. NDNF over-expressed old BMSCs exhibited an antiapoptotic role by upregulating the antiapoptotic gene Bcl-2 and downregulating the proapoptotic genes Bax. Additionally, the protective effects were mediated through the elevation of phosphorylated AKT. Our data support the promise of NDNF as a potential target to enhance the protective effects of autologous aged BMSCs on ischemic cardiomyocytes and then improve the curative effects of stem cell for ischemic heart injury in aged patients.

由于干细胞老化,自体干细胞移植修复心脏的治疗潜力在老年人中逐渐减弱。使衰老干细胞年轻化,以增强其对受伤心肌细胞的保护作用,对老年心力衰竭患者至关重要。在这项研究中,我们旨在研究NDNF的过度表达是否能改善衰老干细胞对损伤心肌细胞的保护作用,并探索其潜在机制。我们从年轻和老年患者身上采集骨髓,并培养 BMSCs。使用携带 NDNF 基因的慢病毒表达载体转染老年 BMSCs。以 H9C2 细胞缺氧诱导的致命性损伤为体外缺血模型。应用不同BMSC组的条件培养基评估其对缺氧诱导的心肌H9C2细胞损伤的有益作用。结果显示,在致命性缺氧条件下,NDNF过度表达的老龄BMSCs的条件培养液能提高H9C2细胞的存活率,降低氧化应激和细胞凋亡水平。过表达 NDNF 的老龄 BMSCs 通过上调抗凋亡基因 Bcl-2 和下调促凋亡基因 Bax 发挥抗凋亡作用。此外,这种保护作用是通过磷酸化 AKT 的升高来介导的。我们的数据支持将NDNF作为潜在靶点,以增强自体老年BMSCs对缺血性心肌细胞的保护作用,进而改善干细胞对老年患者缺血性心脏损伤的治疗效果。
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引用次数: 0
Mice Hepatic Organoids for Modeling Nonalcoholic Fatty Liver Disease and Drug Response. 用于模拟非酒精性脂肪肝和药物反应的小鼠肝脏器官组织。
Pub Date : 2024-08-01 Epub Date: 2024-06-26 DOI: 10.1089/scd.2024.0067
Zheng Zhou, Xiyan Zheng, Maoyun Xie, Zhiqun Lin, Fei Du, Xianjie Shi, Ruixi Li

Nonalcoholic fatty liver disease (NAFLD) is a serious disease. There are no specific drugs for it, in part because of the lack of effective models to aid drug development. However, it has been shown that three-dimensional organoid culture systems can reproduce the organ structure and maintain the gene expression profile of the original tissue. Therefore, we aimed to construct NAFLD models from liver organoids for pharmacological and mechanism studies. We successfully observed morphological changes in normal liver tissue in mouse liver organoids with positive albumin (ALB) expression and potential for differentiation toward hepatocyte-like cells. The mRNA expression of the hepatocyte markers ALB and hepatocyte nuclear factor 4 alpha increased after liver organoid differentiation. We observed free fatty acid (FFA)-induced lipid accumulation in organoids with significant increases in alanine aminotransferase, aspartate aminotransferase, total bilirubin, and triglyceride levels. Moreover, FFA-induced inflammatory cytokines (interleukin-6, tumor necrosis factor-α, and nitric oxide) and fibrosis indicators (collagen type I α1 and laminin α1) were also increased. In addition, RNA sequencing results showed that the expression of key genes [nucleotide oligomerization domain-like receptor (NLR) family apoptosis inhibitory protein, interferon regulatory factor (IRF) 3, and IRF7] involved in NAFLD metabolic abnormalities and insulin resistance in the NLR signaling pathway was altered after FFA induction of the liver organoids. Finally, we found that JC2-11 and lanifibranor limited the FFA-induced increase in oil-red lipid droplets, liver damage, inflammation, and liver fibrosis. In conclusion, tissue structure, gene expression, and the response of mouse liver organoids to drugs can partially mimic in vivo liver tissue. Liver organoids can successfully construct NAFLD models for drug discovery research.

非酒精性脂肪肝(NAFLD)是一种严重的疾病。目前还没有治疗这种疾病的特效药物,部分原因是缺乏有效的模型来帮助药物开发。不过,有研究表明,三维类器官培养系统可以再现器官结构并保持原始组织的基因表达谱。因此,我们旨在利用肝脏类器官构建非酒精性脂肪肝模型,用于药理和机制研究。我们成功地在小鼠肝脏器官组织中观察到了正常肝脏组织的形态学变化,其白蛋白(ALB)表达阳性,具有向肝细胞样细胞分化的潜能。肝细胞标志物 ALB 和肝细胞核因子 4 alpha 的 mRNA 表达在肝脏类器官分化后有所增加。我们观察到游离脂肪酸(FFA)诱导的类器官脂质积累,丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、总胆红素和甘油三酯水平显著增加。此外,FFA 诱导的炎症细胞因子(白细胞介素-6、肿瘤坏死因子-α 和一氧化氮)和纤维化指标(胶原 I 型α1 和层粘连蛋白 α1)也有所增加。此外,RNA测序结果表明,FFA诱导肝脏器官组织后,NOD样受体信号通路中涉及非酒精性脂肪肝代谢异常和胰岛素抵抗的关键基因(NOD样受体家族凋亡抑制蛋白、干扰素调节因子(IRF)3和IRF7)的表达发生了改变。最后,我们发现 JC2-11 和 lanifibranor 限制了 FFA 诱导的油红脂滴增加、肝损伤、炎症和肝纤维化。总之,小鼠肝脏器官组织的组织结构、基因表达和对药物的反应可以部分模拟体内肝脏组织。肝脏器官组织可成功构建非酒精性脂肪肝模型,用于药物发现研究。
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引用次数: 0
Activin A Is a Master Regulator of Phenotypic Switch in Adipose Stromal Cells Initiated by Activated Immune Cell-Secreted Interleukin-1β. 活化素 A 是由活化免疫细胞分泌的 IL-1β 引发的脂肪基质细胞表型转换的主调节因子
Pub Date : 2024-08-01 Epub Date: 2024-07-05 DOI: 10.1089/scd.2024.0092
Sahana Manohar-Sindhu, Stephanie Merfeld-Clauss, Keith L March, Dmitry O Traktuev

Prolonged tissue ischemia and inflammation lead to organ deterioration and are often accompanied by microvasculature rarefaction, fibrosis, and elevated systemic Activin A (ActA), the level of which frequently correlates with disease severity. Mesenchymal stromal cells are prevalent in the perivascular niche and are likely involved in tissue homeostasis and pathology. This study investigated the effects of inflammatory cells on modulation of phenotype of adipose mesenchymal stromal cells (ASC) and the role of ActA in this process. Peripheral blood mononuclear cells were activated with lipopolysaccharide (activated peripheral blood mononuclear cells [aPBMC]) and presented to ASC. Expression of smooth muscle/myofibroblast markers, ActA, transforming growth factors beta 1-3 (TGFβ1-3), and connective tissue growth factor (CTGF) was assessed in ASC. Silencing approaches were used to dissect the signaling cascade of aPBMC-induced acquisition of myofibroblast phenotype by ASC. ASC cocultured with aPBMC or exposed to the secretome of aPBMC upregulated smooth muscle cell markers alpha smooth muscle actin (αSMA), SM22α, and Calponin I; increased contractility; and initiated expression of ActA. Interleukin (IL)-1β was sufficient to replicate this response, whereas blocking IL-1β eliminated aPBMC effects. ASC-derived ActA stimulated CTGF and αSMA expression in ASC; the latter independent of CTGF. Induction of αSMA in ASC by IL-1β or ActA-enriched media relied on extracellular enzymatic activity. ActA upregulated mRNA levels of several extracellular matrix proteins in ASC, albeit to a lesser degree than TGFβ1, and marginally increased cell contractility. In conclusion, the study suggests that aPBMC induce myofibroblast phenotype with weak fibrotic activity in perivascular progenitors, such as ASC, through the IL-1β-ActA signaling axis, which also promotes CTGF secretion, and these effects require ActA extracellular enzymatic processing.

长时间的组织缺血和炎症会导致器官功能衰退,并常常伴有微血管稀疏、纤维化和全身性活化素 A(ActA)升高,而活化素 A 的水平常常与疾病的严重程度相关。间充质基质细胞普遍存在于血管周围的生态位中,很可能参与了组织的稳态和病理过程。本研究调查了炎症细胞对脂肪基质细胞(ASC)表型调节的影响以及 ActA 在这一过程中的作用。外周血单核细胞经 LPS(aPBMC)活化后呈现给 ASC。评估了 ASC 中平滑肌/肌成纤维细胞标记物和 ActA、TGFβ1-3 和 CTGF 的表达。采用沉默法剖析了 aPBMC 诱导 ASC 获得肌成纤维细胞表型的信号级联。与 aPBMC 共同培养或暴露于 aPBMC 分泌物组的 ASC 上调了平滑肌细胞标志物 αSMA、SM22α 和 Calponin I,增加了收缩性,并启动了 ActA 的表达。IL-1β 足以复制这种反应,而阻断 IL-1β 则可消除 aPBMC 的作用。源自 ASC 的 ActA 可刺激 ASC 中 CTGF 和 αSMA 的表达;后者与 CTGF 无关。IL-1β 或富含 ActA 的培养基对 ASC 中 αSMA 的诱导依赖于细胞外酶活性。ActA能上调ASC中几种细胞外基质蛋白的mRNA水平,但上调程度低于TGFβ1,并能轻微增加细胞的收缩性。总之,该研究表明,aPBMC通过IL-1β-ActA信号轴诱导血管周围祖细胞(如ASC)形成具有弱纤维活性的肌成纤维细胞表型,同时促进CTGF的分泌,而这些作用需要ActA胞外酶的处理。
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Stem cells and development
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