Identification of a Hierarchy of Multipotent Hematopoietic Progenitors in Human Cord Blood

Abstract

Mouse hematopoiesis is initiated by long-term hematopoietic stem cells (HSC) that differentiate into a series of multipotent progenitors that exhibit progressively diminished self-renewal ability. In human hematopoiesis, populations enriched for HSC activity have been identified, as have downstream lineage-committed progenitors, but multipotent progenitor activity has not been uniquely isolated. Previous reports indicate that human HSC are enriched in Lin-CD34+CD38- cord blood and bone marrow and express CD90. We demonstrate that the Lin-CD34+CD38- fraction of cord blood and bone marrow can be subdivided into three subpopulations: CD90+CD45RA-, CD90-CD45RA-, and CD90-CD45RA+. Utilizing in vivo transplantation studies and complementary in vitro assays, we demonstrate that the Lin-CD34+CD38-CD90+CD45RA- cord blood fraction contains HSC and isolate this activity to as few as 10 purified cells. Furthermore, we report the first prospective isolation of a population of candidate human multipotent progenitors, Lin-CD34+CD38-CD90-CD45RA- cord blood.

Characterization of the growth modulatory activities of osteoblast conditioned media on cord blood progenitor cells

“…CD38 -CD45RA -CD90 -MPPlike cells (Fig. 2f) (Majeti et al 2007;Notta et al 2011). Finally, production of CB cells with phenotype similar to that of HSC (i.e.…”

Understanding cancer stem cell heterogeneity and plasticity

“…The human HSCs, which are Lin -CD38 -CD45RA -, should better be considered as a hematopoietic stem/progenitor cell pool in which multiple subsets of cells preferentially expressing surface markers, such as CD34 and/or CD90 (Thy-1), (Figure 2) are hierarchically organized. Although it has been known for quite some time that the Lin -CD34 + CD38 -blood cells contain HSCs, most CD34 + cells are actually progenitor cells and the HSC activity can be enriched by CD90 [11]. Nevertheless, even the Lin -CD34 + CD38 -CD45RA -CD90 + subpopulation has only ~5% cells possessing long-term hematopoiesis-reconstituting activity compared to ~1% Lin -CD34 + CD38 -CD45RA -CD90 -cells having such activity [10].…”

How One Thing Led to Another

“…After that, over the next 25 years we identified nearly each step between HSCs and blood cells both in mice (76,78,134,135) and to a lesser extent in humans (136)(137)(138). These have been tested by in vivo transfers and in vitro assays and provide the basis, described below, of knowing the lineage, the function, the life span, and the gene expression profiles of all of these cell types.…”

“…I did not know then to call the selective gene activation epigenetics and completely missed the ideas that the suppressors of gene expression or cell fates could be what we now call tumor suppressor genes. But when we isolated the HSCs and started to understand their behaviors of self-renewal and differentiation through quantal steps of progenitors of everdecreasing fate potential (76,78,(134)(135)(136)(137)(138), I wondered if the self-renewal programs of normal stem cells could be programs that cancer-propagating cells might require, and therefore whether cancers have evolved their own stem cells. These ideas were with me in the mid-1990s, when Sean Morrison was my graduate student and Michael Clarke was on sabbatical in my lab, and when we were pursuing genes that might be involved in HSC self-renewal (151).…”

“…While we were mapping the stages of HSC development to defined progenitors (78,(133)(134)(135)(136)138), we began an experiment to test whether the predilection of granulocytes to die within a day of their genesis could be pathogenic. At that time it became known that the thickened mucus in the lungs and gastrointestinal tract of patients with cystic fibrosis (CF) was mainly DNA and came mainly from granulocytes.…”