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Abstract
A vast literature exists on the biology of blood formation and regeneration under experimental and clinical conditions. The field of hematopoiesis was recently advanced by the capacity to purify to homogeneity primitive hematopoietic stem and progenitor cells. Isolation of cells at defined maturational stages has enhanced the understanding of the fundamental nature of stem cells, including how cell fate decisions are made, and this understanding is relevant to the development of other normal as well as malignant tissues. This review updates the basic biology of hematopoietic stem cells (HSC) and progenitors, the evolving use of purified HSC as grafts for clinical hematopoietic cell transplantation (HCT) including immune tolerance induction, and the application of HSC biology to other stem cell fields.
Keywords bone marrow, embryonic stem cell, transplantation, cancer, autoimmune
INTRODUCTION
Stem cells are cells that, at the single-cell level, both self-renew more stem cells and give rise to clonal progeny that continue to differentiate (1). Thus, hematopoietic stem cells (HSC) are multipotent cells that give rise to more HSC and all formed elements in the blood. Progenitor cells are cells that may be multipotent, oligopotent, or unipotent, and they lack significant self-renewal capacity (1). HSC are entirely responsible for the development, maintenance, and regeneration of blood forming tissues for life (1-4). Furthermore, HSC are the most important, if not the only, cells required to engraft in hematopoietic tissue transplants (3-5). The hematopoietic system is arguably the best characterized among all of the tissues of the human body owing to its unique biological properties, which have allowed both experimental manipulation in preclinical studies and its transplantation into patients who have undergone purposeful ablation of their hematopoietic organ.
Isolation of HSC
The first isolation of HSC required quantitative clonal assays for every blood cell progenitor type (T, B, myeloerythroid) (5-8) and methods to sort cells based on their unique gene expression profiles, as manifested by cell surface proteins and glycoproteins (7-9). Using this approach, both mouse and human HSC were prospectively isolated (8, 9). All HSC activity in adult mouse bone marrow (BM) was shown to be contained in a population marked by the composite phenotype of c-Kit+, Thy-1.1^sub lo^, lineage marker-/^sub lo^ and Sca-1+ (designated KTLS) (3, 10). These KTLS HSC in mice transplanted...