Cooperation between both Wnt/β-catenin and PTEN/PI3K/Akt signaling promotes primitive hematopoietic stem cell self-renewal and expansion

Abstract

Although self-renewal is the central property of stem cells, the underlying mechanism remains inadequately defined. Using a hematopoietic stem and progenitor cell (HSPC)-specific conditional induction line, we generated a compound genetic model bearing both Pten deletion and b-catenin activation. These double mutant mice exhibit a novel phenotype, including expansion of phenotypic long-term hematopoietic stem cells (LT-HSCs) without extensive differentiation. Unexpectedly, constitutive activation of b-catenin alone results in apoptosis of HSCs. However, together, the Wnt/b-catenin and PTEN/PI3k/Akt pathways interact to drive phenotypic LT-HSC expansion by inducing proliferation while simultaneously inhibiting apoptosis and blocking differentiation, demonstrating the necessity of complementary cooperation between the two pathways in promoting self-renewal. Mechanistically, b-catenin activation reduces multiple differentiation-inducing transcription factors, blocking differentiation partially through up-regulation of Inhibitor of differentiation 2 (Id2). In double mutants, loss of Pten enhances the HSC anti-apoptotic factor Mcl-1. All of these contribute in a complementary way to HSC selfrenewal and expansion. While permanent, genetic alteration of both pathways in double mutant mice leads to expansion of phenotypic HSCs, these HSCs cannot function due to blocked differentiation. We developed a pharmacological approach to expand normal, functional HSCs in culture using factors that reversibly activate both Wnt/b-catenin and PI3K/Akt signaling simultaneously. We show for the first time that activation of either single pathway is insufficient to expand primitive HSCs, but in combination, both pathways drive self-renewal and expansion of HSCs with long-term functional capacity.

Overexpression of Aiolos in Nalm-6 acute lymphoblastic leukaemia cells reduces apoptosis by suppressing phosphatase and tensin homologue deleted on chromosome 10 and activating the phosphatidylinositol-3-kinase/Akt signalling pathway

“…Previous studies have demonstrated that, in addition to inhibiting apoptosis, activated Akt can promotes cell cycle progression and cell growth (41)(42)(43). However, the present study revealed that overexpression of Aiolos inhibited the growth of Nalm-6 cells and arrested the cells at the G0/G1 phase.…”

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

“…By heterodimerizing with bHLH proteins (eg, MyoD) Id proteins antagonize differentiation of stem/progenitor cells and also drive the G1/S cell cycle transition in these primitive cells [57,58]. Indeed, Id2 has been found to promote self-renewal or cycling of MSC, HSC and neural stem cells [15,51,[59][60][61]. Moreover, enforced expression of Id2 suppresses OB differentiation by MSC [14].…”

“…GSK3b is inactivated by phosphorylation and promotes activation and nuclear translocation of b-catenin. Recent work by Perry et al showed that b-catenin activation leads to upregulation of Id2 expression that blocks myeloid progenitor differentiation [51]. Western blot analysis for Id2 revealed that SHIP-deficient MSCs express higher levels of protein under undifferentiated growth, but also importantly under osteogenic conditions on a per cell basis (Fig.…”

Regulation of human hematopoietic stem cell self-renewal by the microenvironment’s control of retinoic acid signaling

“…However, the microenvironment's mechanisms responsible for maintaining HSC homeostasis remain unclear. Moreover, our limited current understanding of physiologic selfrenewal of adult human bone marrow-derived HSCs (13) is based largely on data from murine models and umbilical cord blood (14)(15)(16)(17). Here we show that primitive bone marrow CD34 +…”