Rapid and sustained hematopoietic recovery in lethally irradiated mice transplanted with purified Thy-1.1(lo) Lin- Sca-1+ hematopoietic stem cells

N. Uchida, H. L. Aguila, W. H. Fleming, L. Jerabek, I. L. Weissman

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Abstract

Hematopoietic stem cells (HSCs) are believed to play a critical role in the sustained repopulation of all blood cells after bone marrow transplantation (BMT). However, understanding the role of HSCs versus other hematopoietic cells in the quantitative reconstitution of various blood cell types has awaited methods to isolate HSCs. A candidate population of mouse HSCs, Thy-1.1(lo) Lin- Sca-1+ cells, was isolated several years ago and, recently, this population has been shown to be the only population of BM cells that contains HSCs in C57BL/Ka-Thy-1.1 mice. As few as 100 of these cells can radioprotect 95% to 100% of irradiated mice, resulting long-term multilineage reconstitution. In this study, we examined the reconstitution potential of irradiated mice transplanted with purified Thy-1.1(lo) Lin- Sca-1+ BM cells. Donor-derived peripheral blood (PB) white blood cells were detected as early as day 9 or 10 when 100 to 1,000 Thy-1.1(lo) Lin- Sca-1+ cells were used, with minor dose-dependent differences. The reappearance of platelets by day 14 and thereafter was also seen at all HSC doses (100 to 1,000 cells), with a slight dose-dependence. All studied HSC doses also allowed RBC levels to recover, although at the 100 cell dose a delay in hematocrit recovery was observed at day 14. When irradiated mice were transplanted with 500 Thy-1.1(lo) Lin- Sca-1+ cells compared with 1 x 106 BM cells (the equivalent amount of cells that contain 500 Thy-1.1(lo) Lin- Sca-1+ cells as well as progenitor and mature cells), very little difference in the kinetics of recovery of PB, white blood cells, platelets, and hematocrit was observed. Surprisingly, even when 200 Thy-1.1(lo) Lin- Sca- 1+ cells were mixed with 4 x 105 Sca-1- BM cells in a competitive repopulation assay, most of the early (days 11 and 14) PB myeloid cells were derived from the HSC genotype, indicating the superiority of the Thy-1.1(lo) Lin- Sca-1+ cells over Sca-1- cells even in the early phases of myeloid reconstitution. Within the Thy-1.1(lo) Lin- Sca-1+ population, the Rhodamine 123 (Rh123)(hi) subset dominates in PB myeloid reconstitution at 10 to 14 days, only to be overtaken by the Rh123(lo) subset at 3 weeks and thereafter. These findings indicate that HSCs can account for the early phase of hematopoietic recovery, as well as sustained hematopoiesis, and raise questions about the role of non-HSC BM populations in the setting of BMT.

Original languageEnglish (US)
Pages (from-to)3758-3779
Number of pages22
JournalBlood
Volume83
Issue number12
DOIs
StatePublished - 1994

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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