Rapid Lymphocyte Reconstitution of Unconditioned Immunodeficient Mice with Non-Self-Renewing Multipotent Hematopoietic Progenitors

Institute of Cancer and Stem Cell Biology and Medicine, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 07/2006; 5(11):1135-9. DOI: 10.4161/cc.5.11.2772
Source: PubMed


The replacement of abnormal hematopoietic stem cells (HSCs) with normal transplanted HSCs can correct a wide range of hematologic disorders. Here, we provide evidence that transplantation of more differentiated progenitor cells can be used to more rapidly correct lymphoid deficiencies in unconditioned immunocompromised mice. Transplantation of flk2+ multipotent progenitors led to robust B and T cell reconstitution that was maintained for at least 16 weeks. Antigenic challenge at 16 weeks post-transplantation revealed that reconstituted lymphocytes maintained a functional repertoire. In contrast to the persistent lymphocytic engraftment, myeloid chimerism was lost by 12 weeks post-transplantation consistent with the fact that flk2+ progenitors are non-self-renewing. Thus, while more differentiated progenitors are capable of rescuing lymphoid deficiencies, transplantation of HSCs must be used for the correction of non-lymphoid disorders, and, we propose, very long-term immune reconstitution. Based on recent evidence, we discuss novel strategies to achieve the replacement of abnormal HSCs without the use of cytotoxic conditioning regimens.

4 Reads
  • Source
    • "These results highlight the importance of utilizing rigorous stem cell isolation strategies for quantitative evaluation of stem cell function in the context of aging, since assaying stem cell activity based on whole bone marrow, or even KLS cells, as is common in the literature, is extremely problematic due to the enormous changes in stem cell and multipotent progenitor cell frequencies with age (Fig 1B) (Rossi et al., 2005). The use of KLS or whole bone marrow cells to quantitatively assay the lineage potential of stem cells in the context of aging is further confounded by the fact that the multi-potent progenitor subsets contained within the KLS fraction possess substantial long-term lymphoid, yet only transient myeloid reconstituting potential (Adolfsson et al., 2001;Bhattacharya et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Advancing age is frequented by the onset of a variety of hematological conditions characterized by diminished homeostatic control of blood cell production. The fact that upstream hematopoietic stem and progenitor cells are obligate mediators of homeostatic control of all blood lineages, has implicated the involvement of these cells in the pathophysiology of these conditions. Indeed, evidence from our group and others has suggested that two of the most clinically significant age-associated hematological conditions, namely, the diminution of the adaptive immune system and the elevated incidence of myeloproliferative diseases, have their origin in cell autonomous changes in the functional capacity of hematopoietic stem cells.
    Experimental Gerontology 06/2007; 42(5):385-90. DOI:10.1016/j.exger.2006.11.019 · 3.49 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The recent prospective isolation of a wide variety of somatically derived stem cells has affirmed the notion that homeostatic maintenance of most tissues and organs is mediated by tissue-specific stem and progenitor cells and fueled enthusiasm for the use of such cells in strategies aimed at repairing or replacing damaged, diseased, or genetically deficient tissues and organs. Hematopoietic stem cells (HSCs) are arguably the most well-characterized tissue-specific stem cell, with decades of basic research and clinical application providing not only a profound understanding of the principles of stem cell biology, but also of its potential pitfalls. It is our belief that emerging stem cell fields can benefit greatly from an understanding of the lessons learned from the study of HSCs. In this review we discuss some general concepts regarding stem cell biology learned from the study of HSCs with a highlight on recent work pertaining to emerging topics of interest for stem cell biology.
    American Journal Of Pathology 09/2006; 169(2):338-46. DOI:10.2353/ajpath.2006.060312 · 4.59 Impact Factor
Show more


4 Reads
Available from