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TISSUE-SPECIFIC STEM CELLS

Phenotypic and Functional Reversal Within the Early Human Hematopoietic Compartment

^aVirus and Stem Cell Biology Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands;
^bDepartment of Obstetrics and Gynaecology, Rijnland Hospital, Leiderdorp, The Netherlands

Key Words. Hematopoietic stem cells • Feeder layer • Ex vivo cultures • NOD/SCID mouse-repopulating cells • Long-term engraftment • Early lineage markers

Correspondence: Correspondence: Shoshan Knaän-Shanzer, Ph.D., Virus and Stem Cell Biology Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Building 2, Postal Zone S1-P, Einthovenweg 20, 2333 ZC Leiden or P.O. Box 9600, 2300 RC Leiden, The Netherlands. Telephone: 31-71-5269246; Fax: 31-71-5268270; e-mail: s.knaan{at}lumc.nl

Received on February 13, 2008; accepted for publication on September 3, 2008.

First published online in STEM CELLS EXPRESS  September 18, 2008.

The fate of phenotypically defined human hematopoietic stem cells (hHSCs) in culture and the link between their surface marker expression profile and function are still controversial. We studied these aspects of hHSC biology by relating the expression of the early lineage markers (ELM) CD33, CD38, and CD71 on the surface of human umbilical cord blood (UCB) CD34⁺ cells to their long-term nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse repopulation activity (LT-SRA). In uncultured UCB samples, LT-SRA was largely confined to the small CD34⁺ELM^– cell fraction. CD34⁺ cells expressing ELM markers at their surface usually lacked LT-SRA. After culturing UCB CD34⁺ cells for 6 days in serum-free medium and on a feeder layer of Rat2 cells, the number of CD34⁺ELM^– cells stayed roughly the same or showed a slight increase and the LT-SRA was preserved, suggesting a close association between LT-SRA and the CD34⁺ELM^– phenotype. Indeed, transplantation of CD34⁺ELM^– cells isolated from cultured UCB CD34⁺ cells resulted in long-term hematopoietic reconstitution of conditioned NOD/SCID mice, whereas CD34⁺ELM⁺ cells derived from the same cultures were devoid of LT-SRA. Remarkably, roughly 1% of the cells recovered from cultures initiated with isolated CD34⁺ELM⁺ cells had lost ELM surface expression. Concurrently, the cultured CD34⁺ELM⁺ cells acquired LT-SRA, suggesting that hematopoietic stem cells (HSCs) may arise by the dedifferentiation of early hematopoietic progenitor cells. The latter finding challenges the paradigm of unidirectional hematopoietic differentiation and opens new opportunities for HSC expansion prior to transplantation.

Disclosure of potential conflicts of interest is found at the end of this article.