Stable colony stimulating factor 1 fusion protein treatment increases HSC pool and enhances their mobilisation in mice

Abstract

Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with colony stimulating factor-1 (CSF1) to modify the BM niche and expand the potential HSC pool for autologous transplantation. We administrated CSF1 Fc fusion protein (CSF1-Fc) to naive C57Bl/6 mice and assessed the impacts on HSC number and function and overall haematopoiesis. Outcomes were assessed by in situ imaging and ex vivo flow cytometry with functional validation by colony formation and competitive transplantation assay. CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of haematopoiesis was accompanied by an increase in the total available HSPC pool. In the spleen, increased HSC was associated with expression of the BM niche marker CD169 in red pulp macrophages. Pre-treatment with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of granulocyte colony stimulating factor (G-CSF) treatment. These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve autologous or heterologous HSC transplantation outcomes.

Neurogenic Heterotopic Ossifications Recapitulate Hematopoietic Stem Cell Niche Development Within an Adult Osteogenic Muscle Environment

“…They participate in the retention of HSCs through their interactions with MSCs and possibly ECs and the modulation of the expression of proteins such as CXCL12 ( Winkler et al, 2010 ), VCAM-1 and KIT ligand. Furthermore, supraphysiological expansion of the monocyte/macrophage compartment by prolonged administration of a stable recombinant form of macrophage colony-stimulating factor (CSF-1) expand the HSC compartment in the BM ( Kaur et al, 2021 ). Reciprocally, BM-resident macrophages are necessary to reconstitute HSC niches after lethal irradiation and support HSC engraftment ( Kaur et al, 2017 , 2018 ).…”