Identification and characterization of an inhibitor of haemopoietic stem cell proliferation

Abstract

The haemopoietic system has three main compartments: multi-potential stem cells, intermediate stage progenitor cells and mature cells. The availability of simple reproducible culture systems has made possible the characterization and purification of regulators of the progenitor cells, including colony-stimulating factors and interleukins. In contrast, our knowledge of the regulators involved in the control of stem cell proliferation is limited. The steady-state quiescent status of the haemopoietic stem cell compartment is thought to be controlled by locally acting regulatory elements present in the stromal microenvironment, but their purification has been hampered by the lack of suitable culture systems. We have recently developed a novel in vitro colony assay that detects a primitive cell (CFU-A) which has similar proliferative characteristics, in normal and regenerating bone marrow, to the CFU-S (haemopoietic stem cells, as defined by the spleen colony assay) and which responds to CFU-S-specific proliferation regulators. We have now used this assay to purify to homogeneity a macrophage-derived reversible inhibitor of haemopoietic stem cell proliferation (stem cell inhibitor, SCI). Antibody inhibition and sequence data indicate that SCI is identical to a previously described cytokine, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and that SCI/MIP-1 alpha is functionally and antigenically identical to the CFU-S inhibitory activity obtained from primary cultures of normal bone marrow cells. The biological activities of SCI/MIP-1 alpha suggest that it is a primary negative regulator of stem cell proliferation and that it has important therapeutic applications in protecting haemopoietic stem cells from damage during cytotoxic therapies for cancer.

Abl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha

“…Members of the chemokine family have distinct but overlapping biological activities, including stimulating chemotaxis of mature myeloid and lymphoid cells (Oppenheim et al, 1991;Wolpe and Cerami, 1989). Also, some of these chemokines, including Macrophage In¯ammatory Protein-1a (MIP-1a), have a direct growth inhibitory action on haemopoietic progenitor cells Graham et al, 1990). Several cell types, including keratinocytes, exhibit a growth inhibitory response to MIP-1a as well as primitive haemopoietic progenitor cells (Parkinson et al, 1993).…”

Stromal factors support the expansion of the whole hemopoietic spectrum from bone marrow CD34+DR− cells and of some hemopoietic subsets from CD34+ and CD34+DR+ cells

“…Third, macrophage inflammatory protein-1␣ (MIP-1␣) is a negative regulator of hemopoiesis that shows suppressive activity on immature pro-genitors requiring more than one growth factor to proliferate. 27 It has been suggested that MIP-1␣ could enhance hemopoietic progenitor expansion from a primitive cell population by protecting these cells from terminal differentiation. 28 This molecule has also been shown to support the maintenance of LTC-IC from BM CD34 + DR − cells.…”

Characterization of changes in gene expression associated with malignant transformation by the NF-κB family member, v-Rel

“…Speci®cally, MIP-1b stimulates T cell proliferation and induces actin polymerization and profound cytoskeletal changes in T cells within seconds of exposure (Adams et al, 1994). It also exhibits growth regulatory properties for hematopoietic stem and progenitor cells, costimulating myelopoiesis and antagonizing the growth inhibitory activity of MIP-1a (Graham et al, 1990). Our data indicate that overexpression of mip-1b in avian ®broblasts induces cellular transformation as measured by growth in soft agar and extended life span of the cells.…”