The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases

Abstract

Advances in the understanding of the cells of the hematopoietic system have provided a rich basis for improving clinical hematopoietic cell transplants; finding and using proteins and molecules to amplify or suppress particular blood cell types; understanding the stepwise progression of preleukemic stages leading first to chronic myeloid disorders, then the emergence of acute blastic leukemias; and treating malignant and nonmalignant diseases with cell subsets. As a result of intense scientific investigation, hematopoietic stem cells (HSCs) have been isolated and their key functional characteristics revealed-self-renewal and multilineage differentiation. These characteristics are now found to be present in all tissue/organ stem cell studies, and even in the analysis of pluripotent embryonic, nuclear transfer, and induced pluripotent stem cells. Studies on HSC have identified hematopoiesis as one of the best systems for studying developmental cell lineages and as the best for understanding molecular changes in cell fate decision-making and for finding preclinical and clinical platforms for tissue and organ replacement, regeneration, and oncogenesis. Here we review the steps, from our viewpoint, that led to HSC isolation and its importance in self-nonself immune recognition.

Irving L. Weissman

Judith A. Shizuru

Figure 1

Schematic of hematopoietic development indicating intermediates in the hierarchy of hematopoietic differentiation. Surface markers used for isolation are indicated at left for human (top) and mouse (bottom) for each stem and progenitor cell. HSC indicates long-term reconstituting, self-renewing; MPP, multipotent progenitors with limited self-renewal leading to transient but multilineage reconstitution; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; BLP, B lymphocyte protenitor; ProT, T-cell progenitor; GMP, granulocyte/macrophage progenitor; MEP, megakaryocyte/erythroid progenitor; MkP, megakaryocyte progenitor; EP, erythroid progenitor. Adapted from Figure 1 in Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: The paradigmatic tissue specific stem cell. Am J Pathol. 2006;169:338-346, with permission from the American Society for Investigative Pathology.