The role of Wnt signaling in hematopoietic stem cell development

Abstract

Hematopoietic stem cells (HSCs) can self renew and differentiate into all cell types of the blood. This is therapeutically important as HSC transplants can provide a curative effect for blood cancers and disorders. The process by which HSCs develop has been the subject of extensive research in a variety of model organisms, however, efforts to produce bona-fide HSC from pluripotent precursors capable of long term multi-lineage reconstitution have fallen short. Studies in zebrafish, chicken and mice have been instrumental in guiding efforts to derive HSCs from human pluripotent stem cells and have identified a complex set of molecular signals and cellular interactions mediated by such developmental regulators as FGF, Notch, TGFβ and Wnt, which collectively promote the stepwise developmental progression towards mature HSCs. Tight temporal and spatial control of these signals is critical to generate the appropriate numbers of HSCs needed for the life of the organism. The role of the Wnt family of signaling proteins in hematopoietic development has been the subject of many studies owing in part to the complex nature of its signaling mechanisms. By integrating cell fate specification with cell polarity establishment, Wnt is uniquely capable of controlling complex biological processes, including at multiple stages of embryonic HSC development, from HSC specification to emergence from the hemogenic epithelium to subsequent expansion. This review highlights key signaling events where specific Wnt signals instruct and guide hematopoietic development in both zebrafish and mice and extends these findings to current efforts of generating HSCs in vitro.

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

“…Furthermore, the identification of splicing defects in key genes in the WNT pathway, in particular increased TCF7L2 exon 4 inclusion in patient iNCCs, linked with dampened WNT target gene activation, help to explain the WNT signalling defects [81]. However, WNT signalling is involved in the differentiation of a large number of other cell types, including cells of endothelial, cardiac, vascular smooth muscle and haematopoietic lineages, and so defects in other tissues might be expected if the WNT response is defective [89][90][91][92]. While extra-craniofacial abnormalities are seen in some BMKS patients, including congenital heart defects, the facial region is by far the most affected system [4,6].…”

Combination of SB431542, Chir9901, and Bpv as a novel supplement in the culture of umbilical cord blood hematopoietic stem cells

“…Wnt pathway not only plays a critical role in the development of embryonic stem cells [ 33 ], but also in the proliferation and differentiation of adult stem cells including HSCs [ 34 , 35 ]. The major effects of Wnt are applied through β-catenin which can increase the self-renewal and proliferation of HSCs, even independently of the Wnt pathway [ 36 , 37 ].…”

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias

“…Wnt-induced inhibition of GSK3 is best known for its ability to activate b-catenin-driven transcription, which is oncogenic (Nusse and Clevers, 2017). While classic Wnt/b-catenin activating mutations (such as those affecting APC or CTNNB1, which encodes b-catenin) are rare in human leukemias, physiologic Wnt/b-catenin signaling regulates normal and malignant hematopoietic development (reviewed in Lento et al, 2013;Richter et al, 2017;Staal et al, 2016). However, we found that Wnt-induced sensitization to asparaginase was independent of b-catenin, and was instead mediated by Wnt/STOP, which inhibits protein ubiquitination and proteasomal degradation.…”