Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation.

TLDR

The c‑kit receptor and its ligand, steel factor, are known to drive proliferation and differentiation of hematopoietic progenitor cells. The study generated monoclonal antibodies to the extracellular domain of mouse Kit and examined steel‑factor dependence by using Sl/Sl homozygous fetuses that lack functional steel factor. Kit is expressed on a minority of bone marrow cells, including the majority of Thy‑1.1lo Lin‑Sca‑1+ cells enriched for HSCs, and Kit+ subpopulations exhibit colony‑forming and multilineage reconstitution activity, yet Sl/Sl fetuses lacking steel factor show only a modest reduction in HSC numbers early in development, indicating that the Kit‑steel factor interaction is not essential for fetal HSC initiation or self‑renewal.

Abstract

The interaction of the mouse c-kit receptor, designated Kit receptor, and steel factor promotes the proliferation and differentiation of hematopoietic progenitor cells. Monoclonal antibodies against the extracellular portion of the mouse Kit receptor were established. Five percent to 10% of total bone marrow cells expressed the Kit receptor, and half of them lack the expression of lineage markers. The Kit receptor was expressed on 70-80% of Thy-1.1lo Lin-Sca-1+ cells, which express Thy-1.1 antigen at a low level and constitute approximately 0.05% of adult bone marrow and fetal liver; by previous studies, these cells have been shown to be highly enriched for multipotent hematopoietic stem cells (HSCs) and are the only hematopoietic cell subset with this activity. Spleen colony formation and long-term multilineage reconstitution activities were contained in the Kit+ but not in the Kit- subpopulations of Thy-1lo Lin-Sca-1+ cells from adult bone marrow, suggesting that the Kit receptor is expressed on HSCs from the earliest stage-i.e., pluripotent HSCs. The role of steel factor in the development and self-renewal of HSCs was tested with Sl/Sl homozygote fetuses, which lack genes to encode functional steel factor. They were shown to have 30-40% of the number of HSCs on days 13-15 when compared with normal litermates. However, the absolute number of HSCs increased during fetal development in the Sl/Sl mice. The results suggest that the Kit receptor-steel factor interaction may not be essential for the initiation of hematopoiesis and the self-renewal of (at least) fetal HSCs.