Long-term cytokine production from engineered primary human stromal cells influences human hematopoiesis in an in vivo xenograft model

Mo A. Dao, Karen A. Pepper, Jan Nolta

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Human hematopoiesis can be supported in beige/nude/XID (bnx) mice by coinjection of human bone marrow stromal cells engineered to secrete human interleukin 3 (HuIL-3). The major limitation is a total absence of human B cell development in the mice, which could he due to supraphysiological levels of HuIL-3 in the circulation. In an effort to obtain human B lymphoid, as well as T lymphoid and myeloid cell development in the mice, CD34+ cells were coinjected with human marrow stromal cells engineered to secrete human IL-2, IL-7, stem cell factor or FLT3 ligand, ± IL-3. No single factor other than IL-3 supported sustained human hematopoiesis in the mice, although cytokines were expressed for four to six months post-transplantation. Production of both HuIL-3 and IL-7 in the mice supported extrathymic development of human T lymphocytes, but no B cells, myeloid cells, or clonogenic progenitors were detected. Human B cells were not produced front CD34+ cells in the bnx mice under any condition tested. Another limitation to the bnx/Hu system is a lack of maturation of human red blood cells, although BFU-E are maintained. Stromal cells secreting human erythropoietin and IL-3 were cotransplanted into mice with HuCD34+ cells and an increase in hematocrit from 40%-45% to 80%-85% resulted, with production of human and murine red blood cells. Unfortunately, all mice (n = 9) suffered strokes, displayed paralysis and died within three weeks. The bnx/Hu cotransplantation model provides an interesting system in which to study human hematopoietic cell differentiation under the influence of various cytokines.

Original languageEnglish (US)
Pages (from-to)443-454
Number of pages12
JournalStem Cells
Volume15
Issue number6
StatePublished - 1997
Externally publishedYes

Keywords

  • Differentiation
  • Marrow stroma immune deficient mice
  • Retroviral-mediated transduction
  • Stem cells
  • Xenotransplantation

ASJC Scopus subject areas

  • Cell Biology

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