Abstract
Endothelial and mesenchymal stromal cells (ECs/MSCs) are crucial components of hematopoietic bone marrow stem cell niches. Both cell types appear to be required to support the maintenance and expansion of multipotent hematopoietic cells, i.e. hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). With the aim to exploit niche cell properties for experimental and potential clinical applications, we analyzed the potential of primary ECs alone and in combination with MSCs to support the ex vivo expansion/maintenance of human hematopoietic stem and progenitor cells (HSPCs). Even though a massive expansion of total CD34+ HSPCs was observed, none of the tested culture conditions supported the expansion or maintenance of multipotent HSPCs. Instead, mainly lympho-myeloid primed progenitors (LMPPs) were expanded. Similarly, following transplantation into immunocompromised mice the percentage of multipotent HSPCs within the engrafted HSPC population was significantly decreased compared to the original graft. Consistent with the in vitro findings, a bias towards lympho-myeloid lineage potentials was observed. In our conditions, neither classical co-cultures of HSPCs with primary ECs or MSCs, even in combination, nor the xenograft environment in immunocompromised mice efficiently support the expansion of multipotent HSPCs. Instead, enhanced expansion and a consistent bias towards lympho-myeloid committed LMPPs were observed.
Highlights
Self-renewal and differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) need to be highly controlled in order to warrant a life-long supply of mature blood cells
We have shown that human CD133+CD45RA−CD34+ HSPCs are enriched for multipotent HSPCs19
endothelial cells (ECs) were able to take up acetylated low-density lipoprotein (AcLDL), to store Von Willebrand Factor in Weibel-Palade bodies and to form tube-like structures in Matrigel assays (Figs 1C, S2)[34]
Summary
Self-renewal and differentiation of multipotent hematopoietic stem and progenitor cells (HSPCs) need to be highly controlled in order to warrant a life-long supply of mature blood cells. According to the proposed model, multipotent HSPCs can and objectively be identified as CD133 expressing HSPCs containing erythroid differentiation potentials (Fig. 1A)[26] Using this definition as read-out to identify multipotent human HSPCs following in vitro expansion, we recently re-evaluated the reported potential of murine stromal cell lines (AFT024, OP9, MS5) as well as human mesenchymal stromal cell (MSCs) from various tissues to support the ex vivo expansion of UCB-derived HSCs/ MPPs15. In these experiments, none of the tested culture conditions supported the expansion or maintenance of primitive CD133+ HSPCs with erythroid differentiation potentials. All tested conditions demonstrated robust expansion of phenotypical and functional LMPPs
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