Wnt signaling in hematopoietic stem cell maintenance

Abstract

Wnt proteins are known to signal via canonical β-catenin-mediated and non-canonical β-catenin-independent signaling pathways and are involved in various developmental processes. Both Wnt signaling pathways are involved in hematopoietic stem cell (HSC) maintenance, but how they regulate quiescence, proliferation and differentiation is not yet fully understood. In this thesis, I aim to gain insight in the role of Wnt signaling in HSC regulation.

HSCs have the capacity to self-renew, but can also be induced to differentiate into all cells of the hematopoietic compartment. Wnt proteins are secreted by the stromal cells that make up the bone marrow stem cell niche, but are also produced by HSCs themselves. Studies on how Wnt signaling relates to HSC function however yielded contrasting results, with the majority of evidence pointing to a role for Wnt signaling in proliferation and self-renewal. Surprisingly, deletion of β-catenin has no effect on HSC maintenance. In contrast, overexpression of β-catenin results in an increase of HSC proliferation, while stem cells retain an undifferentiated character. Deletion of Wnt3a impairs the self-renewal capacity of HSCs in vivo and consequently, overexpression of Wnt3a results in an increase of proliferation and a block in differentiation. Enforced activation of Wnt signaling pathways, achieved for example by inhibition of GSK-3β or deletion of Apc, results in expansion of the stem cell pool. Non-canonical Wnt signaling via Wnt5a or Wnt4 induces proliferation or provides a signal for quiescence, depending on the context in which signaling occurs.

Together, Wnt signaling appears to play an essential role in regulation of the hematopoietic stem cell pool. Most Wnt signaling pathways seem to promote self-renewal, as they induce proliferation and inhibit differentiation of HSCs. Therefore, Wnt signaling is a crucial factor in the maintenance of this adult stem cell pool.