Concise Review: Regulation of Self-Renewal in Normal and Malignant Hematopoietic Stem Cells by Krüppel-Like Factor 4.

Pluripotent and tissue-specific stem cells, such as blood-forming stem cells, are maintained through a balance of quiescence, self-renewal, and differentiation. Self-renewal is a specialized cell division that generates daughter cells with the same features as the parental stem cell. Although many factors are involved in the regulation of self-renewal, perhaps the most well-known factors are members of the Krüppel-like factor (KLF) family, especially KLF4, because of the landmark discovery that this protein is required to reprogram somatic cells into induced pluripotent stem cells. Because KLF4 regulates gene expression through transcriptional activation or repression via either DNA binding or protein-to-protein interactions, the outcome of KLF4-mediated regulation largely depends on the cellular context, cell cycle regulation, chromatin structure, and the presence of oncogenic drivers. This study first summarizes the current understanding of the regulation of self-renewal by KLF proteins in embryonic stem cells through a KLF circuitry and then delves into the potential function of KLF4 in normal hematopoietic stem cells and its emerging role in leukemia-initiating cells from pediatric patients with T-cell acute lymphoblastic leukemia via repression of the mitogen-activated protein kinase 7 pathway. Stem Cells Translational Medicine 2019;8:568-574.

Primary Human Placental Trophoblasts are Permissive for Zika Virus (ZIKV) Replication.

Zika virus (ZIKV) is an emerging mosquito-borne (Aedes genus) arbovirus of the Flaviviridae family. Although ZIKV has been predominately associated with a mild or asymptomatic dengue-like disease, its appearance in the Americas has been accompanied by a multi-fold increase in reported incidence of fetal microcephaly and brain malformations. The source and mode of vertical transmission from mother to fetus is presumptively transplacental, although a causal link explaining the interval delay between maternal symptoms and observed fetal malformations following infection has been missing. In this study, we show that primary human placental trophoblasts from non-exposed donors (n = 20) can be infected by primary passage ZIKV-FLR isolate, and uniquely allowed for ZIKV viral RNA replication when compared to dengue virus (DENV). Consistent with their being permissive for ZIKV infection, primary trophoblasts expressed multiple putative ZIKV cell entry receptors, and cellular function and differentiation were preserved. These findings suggest that ZIKV-FLR strain can replicate in human placental trophoblasts without host cell destruction, thereby serving as a likely permissive reservoir and portal of fetal transmission with risk of latent microcephaly and malformations.

Host acid sphingomyelinase regulates microvascular function not tumor immunity.

Previous studies provided evidence that MCA/129 fibrosarcomas and B16 melanomas grow 2- to 4-fold faster in acid sphingomyelinase (asmase)-deficient mice than in asmase(+/+) littermates and are resistant to single-dose irradiation due to inability to mount an apoptotic response in tumor microvascular endothelium. However, others postulated the differences might be associated with a host antitumor immune response in asmase(+/+) mice that is not expressed in asmase(-/-) mice due to phenotypic deficiency in antitumor immunity. The present studies demonstrate that none of the tumor-host combinations displayed the classic criteria of an immunogenic tumor because they lacked endotumoral or peritumoral infiltrates almost entirely. Furthermore, neither MCA/129 fibrosarcoma nor B16 melanoma tumors showed differences in growth or radioresponsiveness when implanted into mutant mouse models (Rag(-/-) and MEF(-/-)) lacking functional immune cell [natural killer (NK), NK-T, T, and B cells] populations. Additionally, development and function of B-, T-, and NK-cell populations in asmase(-/-) mice were normal, indistinguishable from their wild-type littermates. These data provide definitive evidence that MCA/129 fibrosarcomas and B16F1 melanomas do not elicit a host immune response in wild-type mice and that the asmase(-/-) phenotype is not deficient in antitumor immunity, supporting the notion that the patterns of tumors growth and radiation response are conditionally linked to the ability of the tumor endothelium to undergo ASMase-mediated apoptosis.