Ide Amber D, Carpenter Kelsey A, Elaswad Mohamed, Opria Katherine, Marcellin Kendersley, Gilliland Carla, Grainger Stephanie
Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956.
bioRxiv. 2025 Jan 10:2025.01.10.632371. doi: 10.1101/2025.01.10.632371.
Hematopoietic stem and progenitor cells (HSPCs) arise only during embryonic development, and their identity specification, emergence from the floor of the dorsal aorta, and proliferation are all tightly regulated by molecular mechanisms such as signaling cues. Among these, Wnt signaling plays an important role in HSPC specification, differentiation, and self-renewal, requiring precise modulation for proper development and homeostasis. Wnt signaling is initiated when a Wnt ligand binds to cell surface receptors such as those encoded by the gene family, activating intracellular signaling pathways that regulate gene expression. Secreted frizzled-related proteins (Sfrps) are known modulators of Wnt signaling, acting as both agonists and antagonists of this pathway. Yet, functions of Sfrps in HSPC development remain incompletely understood. Here, we demonstrate that Sfrp1a regulates zebrafish HSPC development and differentiation in a dose-dependent manner. In Sfrp1a loss of function animals, we observe an increase in HSPCs, an upregulation of canonical Wnt signaling, and a decrease in differentiation into both lymphoid and myeloid lineages. Conversely, at low-dose overexpression, there is a decrease in HSPCs and an increase in lymphoid differentiation. High-dose overexpression phenocopies the loss of function animals, with an increase in HSPCs, increased canonical Wnt signaling, and decreased lymphoid and myeloid differentiation. These findings highlight the importance of dose-dependent modulation of Sfrps, paralleling what is observed in hematopoietic cancers where SFRP1 loss-of-function and gain-of-function variants can drive tumorigenesis.
造血干细胞和祖细胞（HSPCs）仅在胚胎发育期间产生，它们的身份确定、从背主动脉底部出现以及增殖均受到诸如信号线索等分子机制的严格调控。其中，Wnt信号通路在HSPC的确定、分化和自我更新中发挥着重要作用，需要精确调节以实现正常发育和体内平衡。当Wnt配体与细胞表面受体（如由该基因家族编码的受体）结合时，Wnt信号通路被启动，激活调节基因表达的细胞内信号通路。分泌型卷曲相关蛋白（Sfrps）是已知的Wnt信号通路调节剂，可作为该通路的激动剂和拮抗剂。然而，Sfrps在HSPC发育中的功能仍未完全了解。在这里，我们证明Sfrp1a以剂量依赖的方式调节斑马鱼HSPC的发育和分化。在功能缺失的Sfrp1a动物中，我们观察到HSPCs增加、经典Wnt信号上调以及向淋巴系和髓系谱系的分化减少。相反，在低剂量过表达时，HSPCs减少，淋巴系分化增加。高剂量过表达模拟了功能缺失动物的表型，HSPCs增加、经典Wnt信号增加以及淋巴系和髓系分化减少。这些发现突出了Sfrps剂量依赖性调节的重要性，这与在造血癌症中观察到的情况相似，即SFRP1功能缺失和功能获得变体可驱动肿瘤发生。
