Differentiation stage-specific regulation of primitive human hematopoieticprogenitor cycling by exogenous and endogenous inhibitors in an in vivo model

Nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice transplan ted with human cord blood or adult marrow cells and injected 6 weeks posttr ansplant with 2 daily doses of transforming growth factor-beta(1) (TGF-beta (1)), monocyte chemoattractant protein-1 (MCP-1), or a nonaggregating form of macrophage inflammatory protein-1 alpha (MIP-1 alpha) showed unique patt erns of inhibition of human progenitor proliferation 1 day later. TGF-beta( 1) was active on long-term culture initiating cells (LTC-IC) and on primiti ve erythroid and granulopoietic colony-forming cells (HPP-CFC), but had no effect on mature CFC. MCP-I inhibited the cycling of both types of HPP-CFC but not LTC-IC. MIP-1 alpha did not inhibit either LTC-IC or granulopoietic HPP-CFC but was active on erythroid HPP-CFC and mature granulopoietic CFC. All of these responses were independent of the source of human cells trans planted. LTC-IC of either human cord blood or adult marrow origin continue to proliferate in NOD/SCID mice for many weeks, although the turnover of al l types of human CFC in mice transplanted with adult human marrow (but not cord blood) is downregulated after 6 weeks. Interestingly, administration o f either MIP-1 beta, an antagonist of both MIP-1 alpha and MCP-1 or MCP-1(9 -76), an antagonist of MCP-1 (and MCP-2 and MCP-3), into mice in which huma n marrow-derived CFC had become quiescent, caused the rapid reactivation of these progenitors in vivo. These results provide the first definition of s tage-specific inhibitors of human hematopoietic progenitor cell cycling in vivo. In addition they show that endogenous chemokines can contribute to la te graft failure, which can be reversed by the administration of specific a ntagonists. (C) 1999 by The American Society of Haematology.