Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways

Abstract

Genetics and Molecular Biology Branch, National Human Genome Research Institute, Building 49, Room 3A18, 49 Convent Dr., MSC 4442, Bethesda, MD 20892-4442, USA Hematopoietic stem cells (HSCs) are a rare population of cells that are responsible for life-long generation of blood cells of all lineages. In order to maintain their numbers, HSCs must establish a balance between the opposing cell fates of self-renewal (in which the ability to function as HSCs is retained) and initiation of hematopoietic differentiation. Multiple signaling pathways have been implicated in the regulation of HSC cell fate. One such set of pathways are those activated by the Wnt family of ligands. Wnt signaling pathways play a crucial role during embryogenesis and deregulation of these pathways has been implicated in the formation of solid tumors. Wnt signaling also plays a role in the regulation of stem cells from multiple tissues, such as embryonic, epidermal, and intestinal stem cells. However, the function of Wnt signaling in HSC biology is still controversial. In this review, we will discuss the basic characteristics of the adult HSC and its regulatory microenvironment, the "niche", focusing on the regulation of the HSC and its niche by the Wnt signaling pathways.

Networks Establishing Hematopoietic Stem Cell Multipotency and Self-Renewal

“…The Wnt/-catenin signaling pathway also plays a crucial role during self-renewal of HSCs (Nemeth & Bodine, 2007). Deregulation of this pathway has been implicated in the formation of solid tumors, like lung epidermal adenocarcinomas, breast carcinomas and intestinal colorectal tumors just to mention a few (Reya & Clevers, 2005).…”

The Interaction Between Niche and Hematopoietic Stem Cells

“…It was demonstrated that both LRP-5/6 and Frizzled are required to activate functionally the downstream components of the canonical pathway. By now we know there are 19 secreted Wnt ligand glycoproteins, 10 Frizzled receptors, and 2 LRP coreceptors [25][26][27]. At least three different Wnt pathways are currently recognized: the canonical Wnt pathway, the non-canonical Wnt pathway and the planar cell polarity(PCP) pathway.…”

Ex vivo expansion of hematopoietic stem cells

“…Wnt signaling is involved in HSC regulation (reviewed in [59,123]), and Wnt signaling was reported to maintain HSC in a quiescent status in vivo [124]. The effects of Wnt signaling are dosage and context dependent: low Wnt doses result in expansion of HSCs, whereas high doses cause exhaustion [125].…”

“…The abilities of many cytokines to support hematopoietic progenitors to form colonies in vitro provided important insights into expansion of functional primitive long-term (LT-) HSCs that are measured by in vivo repopulating activity [49]. In the last two decades, a number of secreted/extracellular proteins/chemicals have been demonstrated to support ex vivo expansion of mouse HSCs, including stem cell factor (SCF) [50], thrombopoietin (TPO) [51][52][53], Notch ligands [54,55], Wnt ligands [56][57][58][59], fibroblast growth factor 1 (FGF-1) [60,61], bone morphogenetic proteins (BMPs) [62], Hedgehogs [62][63][64], prostaglandin E2 (PGE2) [65], interleukin 10 (IL-10) [66], insulin-like growth factor 2 (IGF-2) [67,68], IGF binding protein 2 (IGFBP2) [69,70], several angiopoietin-like proteins (Angptls) [71][72][73][74], and pleiotrophin [75]. Conditional derivatives of certain growth factor receptors have also been used to support HSC expansion in culture [76,77].…”