Notch2 blockade enhances hematopoietic stem cell mobilization and homing

Abstract

Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation (HCT) may only mobilize limited numbers of hematopoietic progenitor cells (HPCs) into blood, precluding use of the procedure, or being placed at increased risk of complications due to slow hematopoietic reconstitution. Developing more efficacious HPC mobilization regimens and strategies may enhance the mobilization process and improve patient outcome. Although Notch signaling is not essential for homeostasis of adult hematopoietic stem cells (HSCs), Notch-ligand adhesive interaction maintains HSC quiescence and niche retention. Using Notch receptor blocking antibodies, we report that Notch2 blockade, but not Notch1 blockade, sensitizes hematopoietic stem cells and progenitors (HSPCs) to mobilization stimuli and leads to enhanced egress from marrow to the periphery. Notch2 blockade leads to transient myeloid progenitor expansion without affecting HSC homeostasis and self-renewal. We show that transient Notch2 blockade or Notch2-loss in mice lacking Notch2 receptor lead to decreased CXCR4 expression by HSC but increased cell cycling with CXCR4 transcription being directly regulated by the Notch transcriptional protein RBPJ. In addition, we found that Notch2-blocked or Notch2-deficient marrow HSPCs show an increased homing to the marrow, while mobilized Notch2-blocked, but not Notch2-deficient stem cells and progenitors, displayed a competitive repopulating advantage and enhanced hematopoietic reconstitution. These findings suggest that blocking Notch2 combined with the current clinical regimen may further enhance HPC mobilization and improve engraftment during HCT.

CXCL12/CXCR4 Signaling Enhances Human PSC-Derived Hematopoietic Progenitor Function and Overcomes Early In Vivo Transplantation Failure

“…This is sustained through an auto-regulatory loop that is dynamically regulated from cell surface to intracellular stores ( Lapidot and Kollet, 2002 ). CXCR4 is regulated by BM factors, some of which include hypoxia ( Scheurer et al., 2004 ), Notch ( Wang et al., 2017 ), glucocorticoid ( Guo et al., 2017 ), and prostaglandin E 2 (PGE 2 ) ( Goessling et al., 2011 ) signaling pathways. However, the functional capacity of hPSC-HPCs to respond to BM regulatory cues remains largely unknown.…”

Physiological Cues Involved in the Regulation of Adhesion Mechanisms in Hematopoietic Stem Cell Fate Decision

“…Deletion of Notch1 alone, or Notch1 and Notch2 together was found to increase the differentiation of lymphoid HSCs ( Bigas and Espinosa, 2012 ). Wang et al (2017) found that Notch 2, but not Notch 1, blockade leads to HSC mobilization. Interestingly, Notch 2 blocked, but not Notch 2 deficient, HSCs exhibited a competitive repopulating advantage and enhanced hematopoietic reconstitution.…”

A Review of Advances in Hematopoietic Stem Cell Mobilization and the Potential Role of Notch2 Blockade

“…We found that in mice receiving Notch2-blocking antibodies, but not Notch1-blocking antibodies, spleen-residing LSKs and LKs increased three- to four-fold. When mice were given G-CSF and plerixafor following four doses of anti-Notch2 treatment, a 2.5-fold increase of white blood cells, a 3- and 3.3-fold increase of LSKs and LKs were seen in the periphery, and a 3.6- and 2-fold increase of spleen-residing LSKs and LKs were found in mice receiving anti-Notch2 compared to control-treated mice 116 . However, Notch2 blockade, combined with G-CSF or plerixafor, did not affect marrow HSPC homeostasis.…”