PTPN13 and β-Catenin Regulate the Quiescence of Hematopoietic Stem Cells and Their Interaction with the Bone Marrow Niche

Abstract

SummaryThe regulation of hematopoietic stem cells (HSCs) depends on the integration of the multiple signals received from the bone marrow niche. We show the relevance of the protein tyrosine phosphatase PTPN13 and β-catenin as intracellular signaling molecules to control HSCs adhesiveness, cell cycling, and quiescence. Lethally irradiated mice transplanted with Lin– bone marrow cells in which PTPN13 or β-catenin had been silenced showed a significant increase of long-term (LT) and short-term (ST) HSCs. A decrease in cycling cells was also found, together with an increase in quiescence. The decreased expression of PTPN13 or β-catenin was linked to the upregulation of several genes coding for integrins and several cadherins, explaining the higher cell adhesiveness. Our data are consistent with the notion that the levels of PTPN13 and β-catenin must be strictly regulated by extracellular signaling to regulate HSC attachment to the niche and the balance between proliferation and quiescence.

Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

“…Several known signals play a large role in inducing and sustaining hematopoiesis, such as the NOTCH [81], mTOR [93], and Wnt/b-catenin pathways [94][95][96]. Several known signals play a large role in inducing and sustaining hematopoiesis, such as the NOTCH [81], mTOR [93], and Wnt/b-catenin pathways [94][95][96].…”

“…To date, the full HSC in vivo niche remains incompletely understood, complicating attempts to reconstruct this complex signaling system in vitro. Several known signals play a large role in inducing and sustaining hematopoiesis, such as the NOTCH [81], mTOR [93], and Wnt/b-catenin pathways [94][95][96].…”

Microenvironmental regulation of hematopoietic stem cells and its implications in leukemogenesis

“…Wnt regulation of HSCs appears to be mediated in part through its effects on HSC adhesion in the niche. Two downstream effectors of Wnt, β-catenin and the phosphatase PTPN13, are important in this process [37, 38*]. Knockdown of these effectors in murine Lin − cells increased the fraction of LT-HSCs, increased HSC and progenitor adhesion in the BM, decreased cell cycling and proliferation, and was associated with upregulation of several CAM genes ( ITGA4, CDH1, CDH12, NCAM2, and RELN ) [38*].…”

“…Two downstream effectors of Wnt, β-catenin and the phosphatase PTPN13, are important in this process [37, 38*]. Knockdown of these effectors in murine Lin − cells increased the fraction of LT-HSCs, increased HSC and progenitor adhesion in the BM, decreased cell cycling and proliferation, and was associated with upregulation of several CAM genes ( ITGA4, CDH1, CDH12, NCAM2, and RELN ) [38*]. Notably, this effect was seen in vivo in transplantations studies and in co-culture with MSCs, but not in isolated Lin − cultures or co-cultures with MSCs in transwell devices, demonstrating the importance of physical interactions of HSCs with niche stromal cells.…”

The DARC-CD82 axis discloses bone marrow macrophages as guardians of long-term hematopoietic stem cells quiescence

“…CD82 has been previously described as a regulator of cell adhesion through control of alpha 4 integrin (28). We and others have demonstrated the importance of cell adhesion molecules in the regulation of HSC quiescence (10,11,23,29,30). Therefore, we would not discard the possibility that, in addition to TGF-β signaling, cell adhesion might have a role in CD82-mediated control of the cell cycle.…”