Diverse isoforms of colony‐stimulating factor‐1 have different effects on the development of stroma‐dependent hematopoietic cells

Abstract

Maintenance and differentiation of hematopoietic stem and progenitor cells are controlled by complex interactions with the stroma microenvironment. Stroma-cell interactions can be supported by locally expressed membrane-spanning cell-surface (cs) growth factors. CSF-1 is expressed by stroma as a soluble glycoprotein, as proteoglycan, or as a membrane-spanning cs glycoprotein. CSF-1 regulates the survival, proliferation, and differentiation of mononuclear phagocytes. Whereas the biological role of soluble CSF-1 is well characterized, the function of the membrane-spanning cell-surface CSF-1 (csCSF-1) remains unclear. To analyze the biological significance of csCSF-1 in vitro, we used an epithelial cell line to ectopically express the different CSF-1 isoforms. In co-cultures of CSF-1 transduced epithelial cells with primary, early hematopoietic progenitor cells we examined whether interaction between csCSF-1 and its receptor mediates cell proliferation, self-renewal, or differentiation. csCSF-1 induces long-lasting proliferation of stimulated cells and furthermore supports self-renewal. Ectopic secretion of soluble CSF-1 does not permit long-term growth of progenitor cells but induces differentiation of monocytes into macrophages. Previously, we showed that the soluble and cs isoforms of stroma-encoded SCF differently affect the development of hematopoietic cells. Cell-surface SCF (csSCF) promotes self-renewal of stimulated cells whereas soluble SCF causes clonal extinction. These results and those presented here for CSF-1 provide evidence for diverse functions of the isoforms of the ligands SCF and CSF-1 for two tyrosine kinase receptors of the subclass III both regulating hematopoiesis on stroma.

Involvement of CSF‐1 in generating a stroma‐independent hematopoietic stem cell line

“…Indeed, it is assumed by many that the CSF-1/CSF-1 receptor system mainly regulates commitment to the macrophage lineage and influences maturation of late progenitors to functional macrophages. Consistent with the early observations, and with our recent observations that CSF-1 can replace SCF as a stem cell factor in sustaining early cells (Friel et al, 2005), we show here that CSF-1 similar to SCF functions as an inducer of proliferation of hematopoietic stem cells.…”

“…The two receptors also show high homology and have evolved from a common ancestor gene (Qiu et al, 1988). Thus, cell-surface CSF-1 most likely is similar to SCF in exerting an important role in stimulating the long-term survival of early hematopoietic progenitors (Friel et al, 2002(Friel et al, , 2005.…”

Selective deletion of the membrane-bound colony stimulating factor 1 isoform leads to high bone mass but does not protect against estrogen-deficiency bone loss

“…Indeed recent findings have suggested that IL-34 and CSF1 bind to different domains of c-fms resulting in differing bioactivities and signal activation kinetics and signal strength [18]. With regard to the differing actions of mCSF1 and sCSF1, Friel et al [19] reported that mCSF1 supported long-term proliferation of hematopoietic precursor cells as well as self-renewal of this population. In contrast, sCSF1 did not support a self-renewing population of progenitors but rather drove cells to differentiate into monocytes and macrophages.…”

Engineering the hematopoietic stem cell niche: Frontiers in biomaterial science

“…Interestingly, matrix-immobilized forms of these cytokines (e.g. macrophage colony-stimulating factor or M-CSF [71], SCF [72, 73]) may provide better support for long-term in vitro expansion of HSCs than soluble forms. A wider range of additional factors, notably Ang-1, OPN, IL-7, and VCAM [10] can also affect HSC fate decisions.…”

“…Stromal cells are commonly included in early efforts aimed at ex vivo expansion of HSCs [69, 120]. Here, culture with bone marrow-derived stromal cells [71, 121], MSCs [122], osteoblasts [45], and vascular endothelial cells [53, 54, 58] have been shown to effect long-term HSC maintenance and expansion. Feeder cell layers are commonly used to promote the differentiation of HSCs into myeloid (e.g.…”