Cell Proliferation

IF 2021: 8.755

CATEGORY: 53/193 (Cell Biology)

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Cell Proliferation所出版的前沿文章都是经过严格、公平的同行评议流程，并采用最高质量的制作标准呈现，务求打造最优质的开放获取期刊。自2017年起，由周琪院士担任主编。2019年，Cell Proliferation成为中国细胞生物学学会干细胞分会旗舰期刊，2021年由周琪院士担任理事长的北京干细胞与再生医学研究院与Wiley达成长期战略合作，共同培育在细胞生物学和细胞医学领域具有国际影响力的顶级SCI学术期刊。

目前，Cell Proliferation被认为是癌症和干细胞研究领域的主要参考文献，刊登干细胞、细胞衰老、再生医学、细胞死亡、组织工程等与细胞增殖和分化相关的重要研究成果。文章类型包括综述、病例报道、原创性研究、干细胞标准、会议报告等。

Epidermal growth factor induces a trophectoderm lineage transcriptome resembling that of human embryos during reconstruction of blastoids from extended pluripotent stem cells

表皮生长因子EGF在从扩展多能干细胞重建类囊胚的过程中诱导类似于人类胚胎产生的滋养外胚层谱系转录组

Yingying Zhang, Chenrui An, Yanhong Yu, Jiajing Lin, Long Jin, Chaohui Li, Tao Tan, Yang Yu, Yong Fan

First published: 26 July 2022

目的：本研究旨在通过添加EGF优化人类扩展多能干细胞（EPSC）向滋养外胚层（TE）样细胞的诱导过程，并提高重建类囊胚的质量。

材料和方法：TE样细胞由人EPSCs分化而来。运用RNA-seq数据分析，将其与来自多种人类多能干细胞（hPSCs）和胚胎的TE样细胞进行比较。为了优化TE样细胞诱导，进行了小规模的化合物筛选，并利用TE谱系标记物的免疫荧光染色表征其诱导效率。利用优化的TE样细胞和未分化的人EPSCs通过三维培养系统生成了类囊胚。进行单细胞RNA测序以研究优化的类囊胚与人囊胚的谱系分离。

结果：来源于人EPSCs的TE样细胞与胚胎来源的TE细胞表现出相似的转录组。此外，来自多种原始hPSCs的TE样细胞表现出异质的基因表达模式和信号通路，因为原始特异性基因的不完全沉默和印记的丧失。此外，随着EGF的添加，源自人类EPSCs的TE样细胞增强了TE谱系相关的信号通路，并表现出与人类胚胎更相似的转录组。通过模拟未分化的人EPSCs，我们提高了重建类囊胚的质量和效率，并分离了更多具有精确时空表达的谱系细胞，尤其是PE谱系。

结论：添加EGF可增强TE谱系分化和人类囊胚重建。优化的类囊胚可用作模拟早期胚胎发育的囊胚模型。

‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍‍Objectives: This study aims to optimize the human extended pluripotent stem cell (EPSC) to trophectoderm (TE)-like cell induction with addition of EGF and improve the quality of the reconstructing blastoids.

Materials and Methods: TE-like cells were differentiated from human EPSCs. RNA-seq data analysis was performed to compare with TE-like cells from multiple human pluripotent stem cells (hPSCs) and embryos. A small-scale compound selection was performed for optimizing the TE-like cell induction and the efficiency was characterized using TE-lineage markers expression by immunofluorescence stanning. Blastoids were generated by using the optimized TE-like cells and the undifferentiated human EPSCs through three-dimensional culture system. Single-cell RNA sequencing was performed to investigate the lineage segregation of the optimized blastoids to human blastocysts.

Results: TE-like cells derived from human EPSCs exhibited similar transcriptome with TE cells from embryos. Additionally, TE-like cells from multiple naive hPSCs exhibited heterogeneous gene expression patterns and signalling pathways because of the incomplete silencing of naive-specific genes and loss of imprinting. Furthermore, with the addition of EGF, TE-like cells derived from human EPSCs enhanced the TE lineage-related signalling pathways and exhibited more similar transcriptome to human embryos. Through resembling with undifferentiated human EPSCs, we elevated the quality and efficiency of reconstructing blastoids and separated more lineage cells with precise temporal and spatial expression, especially the PE lineage.

Conclusion: Addition of EGF enhanced TE lineage differentiation and human blastoids reconstruction. The optimized blastoids could be used as a blastocyst model for simulating early embryonic development.

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Inhibition of L-type voltage-gated calcium channel-mediated Ca²⁺ influx suppresses the collective migration and invasion of ameloblastoma

抑制L型电压门控钙通道介导的Ca²⁺内流抑制成釉细胞瘤的集体迁移和侵袭

Shujin Li, Hyun-Yi Kim, Dong-Joon Lee, Sung-Ho Park, Keishi Otsu, Hidemitsu Harada, Young-Soo Jung, Han-Sung Jung

First published: 06 July 2022

目的：成釉细胞瘤（AM）是一种良性但有局部侵袭性的肿瘤，复发率较高。AM 的侵袭行为会导致相邻颌骨的破坏和手术过程中无法检测到的病灶残余，从而影响癌细胞的完全清除。

方法：为了探索肿瘤细胞侵袭的新靶点，通过二代测序技术进行了 AM 和牙源性角化囊肿之间的详细转录组学分析。

结果：首次观察到L型电压门控钙通道（VGCC）亚基，CACNA1C基因（编码Cav1.2通道）在AM中的富集。通过患者样本或原代细胞中的免疫染色和钙成像证实了 Cav1.2 的表达和通道活性。一种L 型 VGCC 阻滞剂，Verapamil在体外显示抑制 Ca²⁺诱导的细胞聚集和 AM 细胞的集体侵袭。此外，Verapmil抑制AM侵入相邻骨骼的作用通过原位异种移植模型得到证实。

结论：综上所述，Cav1.2 可能被认为是减少 AM 的集体迁移和侵袭的治疗候选靶点。

‍‍‍Objectives: Ameloblastoma (AM) has been known as a benign but locally invasive tumour with high recurrence rates. Invasive behaviour of the AM results in destruction of the adjacent jawbone and the non-detectable remnants during surgery, interrupting the complete elimination of cancer cells.

Methods: To explore novel targets for the tumour cell invasion, a transcriptomic analysis between AM and odontogenic keratocyst were performed through next-generation sequencing in detail.

Results: Enrichment of CACNA1C gene (encoding Cav1.2) in AM, a subunit of the L-type voltage-gated calcium channel (VGCC) was observed for the first time. The expression and channel activity of Cav1.2 was confirmed by immunostaining and calcium imaging in the patient samples or primary cells. Verapamil, L-type VGCC blocker revealed suppression of the Ca2+ -induced cell aggregation and collective invasion of AM cells in vitro. Furthermore, the effect of verapamil in suppressing AM invasion into the adjacent bone was confirmed through orthotopic xenograft model specifically.

Conclusion: Taken together, Cav1.2 maybe considered to be a therapeutic candidate to decrease the collective migration and invasion of AM.

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Inducible motor neuron differentiation of human induced pluripotent stem cells in vivo

体内的诱导多能干细胞诱导运动神经元分化

Min Chen, Xia Wang, Chuan Li, Ting Lan, Yuhui Wei, Chengcheng Tang, Xiaoqing Zhou, Renping Zhou, Alessandro Rosa, Xi Zheng, Song Ang, Kun Zhang, Qingjian Zou, Liangxue Lai

First published: 09 August 2022

目的：移植源自人类诱导多能干细胞 (hiPSCs) 的神经祖细胞 (NPCs) 是运动神经元疾病 (MNDs) 有前景的治疗策略之一。然而，在体内 NPCs 定向分化的低效率限制了其应用。在这里，我们试图通过使用运动神经元 (MN) 特异性转录因子和 Tet-On 系统来实现 hiPSCs 的体内定向分化，从而建立 MND 的潜在治疗策略。

材料和方法：我们用3种 MN 特异性转录因子和 Tet-On 系统改造了 hiPSCs。改造后的细胞通过皮下、脊髓内或脑室内注射被直接移植到免疫缺陷小鼠体内。在强力霉素 (Dox) 诱导后，评估了畸胎瘤的形成和运动 MN 分化情况。

结果：我们生成了基因工程改造后的 hiPSCs，其中 Ngn2、Isl1 和 Lhx3 的表达由药物诱导的转基因系统控制。这些细胞表现出正常的多能性和增殖能力，在 Dox 的诱导下，能够在脊髓和大脑侧脑室中高效定向分化为成熟运动神经元 (MNs) 和 NPCs。移植物在受体小鼠中显示出长期存活性，没有形成畸胎瘤。

结论：诱导产生的成熟 MNs 有望直接替代受损的内源性 MNs，诱导产生的NPCs可以为长期神经元损伤修复发挥从头干细胞储备的作用。因此，通过  MN 特异性转录因子和 Dox诱导的Tet-On 系统实现 hiPSCs 体内定向分化可能是一种具有高效性和安全性的潜在 MND 治疗策略。

‍‍Objectives: Transplantation of neural progenitor cells (NPCs) derived from human-induced pluripotent stem cells (hiPSCs) is one of the promising treatment strategies for motor neuron diseases (MNDs). However, the inefficiency in committed differentiation of NPCs in vivo limits its application. Here, we tried to establish a potential therapeutic strategy for MNDs by in vivo directional differentiation of hiPSCs engineered with motor neuron (MN) specific transcription factors and Tet-On system.

Materials and methods: We engineered hiPSCs with three MN-specific transcription factors and Tet-On system. The engineered cells were directly transplanted into immunodeficient mice through subcutaneous, intra-spinal cord and intracerebroventricular injections. Following doxycycline (Dox) induction, teratoma formation, and motor MN differentiation were evaluated.

Results: We generated genetically engineered hiPSCs, in which the expression of Ngn2, Isl1, and Lhx3 was controlled by a drug-inducible transgenic system. These cells showed normal pluripotency and proliferative capacity, and were able to directionally differentiate into mature motor neurons (MNs) and NPCs with high efficiency in spinal cords and cerebral lateral ventricles under the induction of Dox. The grafts showed long-term survival in the recipient mice without formation of teratoma.

Conclusions: The induced mature MNs and NPCs were expected to replace the damaged endogenous MNs directly, and play a role of de novo stem cell stock for long-term neuron damage repair, respectively. Therefore, in vivo directional differentiation of the hiPSCs engineered with MN-specific transcription factors and Tet-On system via Dox induction could be a potential therapeutic strategy for MNDs with high efficacy and safety.

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翻译 | 赵一鸣

排版 | 赵一鸣 王子钺

审核 | 查昭

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