The homeodomain transcription factor Octamer-binding transcription factor 4 (OCT4), also known as POU domain, class 5, transcription factor 1 (POU5F1), represents one of the crucial factors that maintain the self-renewal of human and mouse pluripotent stem cells.^{1, 2} OCT4 expression also characterizes the cells of the inner cell mass of the developing blastocyst and is considered a marker of embryonic stem cells (ESCs). The reprogramming of somatic cell types into induced pluripotent stem cells (iPSCs) generally involves either the forced expression of OCT4 (alongside factors such as SOX2, KLF4, MYC, LIN28, and NANOG) or includes the induction of endogenous OCT4 expression as a means to “kick-start” pluripotency.³ On the contrary, the differentiation of pluripotent stem cells generally requires OCT4 silencing; meanwhile, later OCT4 expression/reactivation has been linked to tumorigenesis and has been linked with therapeutic resistance and worse prognosis.⁴ Recent OCT4-focused research efforts have sought to decipher how external forces acting upon pluripotent stem cells prompt the increased expression of pluripotency-associated genes, such as OCT4, and explore the contribution of OCT4 in the reprogramming of cells of species other than human, mouse, rat, or monkey into iPSCs.³ In our first Featured Article published this month in STEM CELLS, Nath et al describe how the fluid shear stress generated during bioreactor culture helps to maintain the pluripotency of mouse ESCs through the upregulated expression of Oct4, Sox2, and Nanog - a phenomenon they term “mechanopluripotency.”⁵ In a Related Article published recently in STEM CELLS Translational Medicine, Questa et al identified the alterations to the global chromatin landscape that occur during the OCT4, SOX2, KLF4, and MYC-induced reprogramming of canine cells and define candidate barriers that prevent adult canine cells from undergoing efficient reprogramming.⁶

Wnt signaling comprises one of the crucial developmental signaling pathways that control cell fate decisions and tissue patterning during embryonic development and supports the self-renewal, proliferation, and differentiation of a range of tissue-specific stem cells⁷ that include neural stem cells⁸ and epidermal stem cells.⁹ Notably, multiple studies have linked deregulated Wnt signaling to tumorigenesis in the skin, breast, bone marrow, and colon tissue and to degenerative diseases such as sclerosteosis and hereditary osteoporosis.¹⁰ Wnt signaling comprises three known pathways activated by the binding of a Wnt-protein ligand to a Frizzled family receptor but that possess unique transduction cascades involving specific proteins. The canonical β-catenin pathway involves the stabilization and transport of β-catenin into the nucleus where it supports the transcription of Wnt target genes. Meanwhile, the Wnt/planar cell polarity (PCP) pathway mediates cytoskeletal organization and cell polarity by acting on the actin cytoskeleton and the Wnt/Ca²⁺ pathway mediates the release of intracellular calcium. Recent research has sought to understand the role of Wnt signaling in hematopoietic stem cells (HSCs) and explore Wnt antagonism as a means to direct stem cell fate for regenerative purposes. In our second Featured Article published this month in STEM CELLS, Hétu-Arbour et al provide evidence that expression of the noncanonical ligand Wnt4 by HSCs enhances blood cell production in a study that may prompt the development of advanced post-chemotherapy treatments.¹¹ In a Related Article published recently in STEM CELLS Translational Medicine, Negri et al reported that the neutralization of a Wnt signaling antagonist induced the osteogenic differentiation of human adipose-derived mesenchymal stem cells (ASCs) and supported engraftment, survival, and improved bone repair outcomes in a mouse femoral segmental bone defect model.¹²

同源域转录因子八聚体结合转录因子 4 (OCT4)，也称为 POU 域，第 5 类，转录因子 1 (POU5F1)，是维持人和小鼠多能干细胞自我更新的关键因素之一。^{1, 2} OCT4表达也表征发育中的囊胚内细胞团的细胞，并且被认为是胚胎干细胞 (ESC) 的标志物。将体细胞类型重编程为诱导多能干细胞 (iPSC) 通常涉及OCT4的强制表达（以及SOX2、KLF4、MYC、LIN28和NANOG 等因素）) 或包括诱导内源性OCT4表达作为“启动”多能性的一种手段。³相反，多能干细胞的分化一般需要OCT4沉默；同时，后来的OCT4表达/再激活与肿瘤发生有关，并与治疗抵抗和较差的预后有关。⁴最近以OCT4 为重点的研究努力试图破译作用于多能干细胞的外力如何促使多能相关基因（如OCT4）的表达增加，并探索OCT4的贡献将人类、小鼠、大鼠或猴子以外的物种细胞重编程为 iPSC。³在我们本月在STEM CELLS 上发表的第一篇专题文章中，Nath 等人描述了生物反应器培养过程中产生的流体剪切应力如何通过Oct4、Sox2和Nanog的上调表达来帮助维持小鼠 ESC 的多能性——他们称之为这种现象。 “机械多能性。” ⁵在最近发表在STEM CELLS Translational Medicine 上的一篇相关文章中，Questa 等人确定了在OCT4、SOX2、KLF4期间发生的全局染色质景观的改变和MYC诱导的犬细胞重编程，并定义了阻止成年犬细胞进行有效重编程的候选障碍。⁶

Wnt 信号包括控制胚胎发育过程中细胞命运决定和组织模式的关键发育信号通路之一，并支持一系列组织特异性干细胞⁷的自我更新、增殖和分化，包括神经干细胞⁸和表皮干细胞。⁹值得注意的是，多项研究已将 Wnt 信号失调与皮肤、乳房、骨髓和结肠组织的肿瘤发生以及硬化症和遗传性骨质疏松症等退行性疾病联系起来。¹⁰Wnt 信号传导包括通过 Wnt 蛋白配体与卷曲家族受体结合而激活的三种已知途径，但这些途径具有涉及特定蛋白质的独特转导级联。经典的 β-catenin 通路涉及 β-catenin 的稳定化和转运到细胞核中，在那里它支持 Wnt 靶基因的转录。同时，Wnt/平面细胞极性 (PCP) 通路通过作用于肌动蛋白细胞骨架和 Wnt/Ca ^{2+ 来}介导细胞骨架组织和细胞极性。通路介导细胞内钙的释放。最近的研究试图了解 Wnt 信号在造血干细胞 (HSC) 中的作用，并探索 Wnt 拮抗作用作为指导干细胞命运以实现再生目的的一种手段。在我们本月在STEM CELLS 上发表的第二篇专题文章中，Hétu-Arbour 等人提供的证据表明，HSC 表达非经典配体 Wnt4 可增强血细胞生成，该研究可能会促进先进的化疗后治疗的发展。¹¹在最近发表在STEM CELLS Translational Medicine 上的相关文章中, Negri 等人报道，Wnt 信号传导拮抗剂的中和诱导人脂肪来源间充质干细胞 (ASC) 的成骨分化，并支持小鼠股骨节段性骨缺损模型的植入、存活和改善骨修复结果。¹²