Hemopoietic precursor cell defects in nonanemic but stem cell‐deficient W44/W44 mice

Abstract

Hematopoietic stem cell deficiencies cause a severe macrocytic anemia in W/W″ mice. W⁴⁴/W⁴⁴ mice, on the other hand, are not anemic, but, since they accept marrow implants without prior total body irradiation, they have inherited a stem cell lesion. In an attempt to identify the aberrant stem cell(s), we have determined the concentration in W⁴⁴/W⁴⁴ marrow of hematopoietic precursors known to be deficient in W/W^v marrow. The in vitro erythroid burst-forming units (BFU-E), the in vivo spleen colony-forming units (CFU-S), and the cells that repopulate the erythroid compartment of stem cell-deficient mice were examined. The progenitors of 7-day bursts are dramatically reduced in W/W″ marrow but are present in normal concentrations in W⁴⁴/W⁴⁴ marrow. W⁴⁴/W⁴⁴ marrow CFU-S, unlike W/W″, generate visible spleen colonies 10 days after injection into lethally irradiated recipients. The colonies are, however, smaller and at least 2 times less numerous than those produced from equivalent numbers of +/+ marrow. An additional defect was the inability of W⁴⁴/W⁴⁴ stem cells to compete with genetically marked +/+ cells during erythroid repopulation. An estimate of the number of W⁴⁴/W⁴⁴ stem cells needed to compete with +/+ cells was provided by enriching W⁴⁴/W⁴⁴ progenitors fivefold. Twice as many enriched W⁴⁴/W⁴⁴ marrow cells as unfractionated +/+ cells were required to replace competitor cells. This suggests that there are up to 10 times fewer stem cells somewhere in the W⁴⁴/W⁴⁴ erythrogenerative pathway. The data support the conclusion that an erythroid progenitor less mature than the BFU-E is one of the cells most severely affected by expression of the mutant gene.