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Fast But Durable Megakaryocyte Repopulation and Platelet Production in NOD/SCID Mice Transplanted with Ex-Vivo Expanded Human Cord Blood CD34⁺ Cells

^a Department of Oncological Sciences, University of Torino Medical School,
^b Division of Clinical Oncology, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy;
^c The Pediatric Department, University of Torino Medical School, Torino, Italy

Key Words. Cord blood • CD34⁺ cell expansion • NOD/SCID • Megakaryocyte engraftment

Wanda Piacibello, M.D., University of Torino Medical School, Department of Oncological Sciences, Institute for Cancer Research and Treatment, Laboratory of Clinical Oncology, Prov. 142, 10060 Candiolo, Torino, Italy. Telephone: 39-011-9933349; Fax: 39-011-9933522; e-mail: wanda.piacibello{at}ircc.it

We have previously established a stroma-free culture with Flt-3 ligand (FL), stem cell factor (SCF), and thrombopoietin (TPO) that allows the maintenance and the expansion for several weeks of a cord blood (CB) CD34⁺ cell population capable of multilineage and long-lasting hematopoietic repopulation in non-obese diabetic/ severe combined immunodeficient (NOD/SCID) mice.

In this work the kinetics of megakarocyte (Mk)-engraftment that is often poor and delayed in CB transplantation, and human platelet (HuPlt) generation in NOD/SCID mice of baseline CD34⁺ cells (b34⁺), and of CD34⁺ cells reisolated after a 4-week expansion with FL+SCF+TPO (4w34⁺) were compared.

With b34⁺ cells Mk-engraftment was first seen at week 3 (CD41⁺: 0.4%); 4w34⁺ cells allowed a more rapid Mk-engraftment (at weeks 2 and 3 the CD41⁺ cells were 0.3% and 0.8%). Circulating HuPlts were first seen at weeks 2 and 1, respectively.

Mk-engraftment levels of b34⁺ and 4w34⁺ cells 6–8 weeks after transplantation were similar (12 ± 3.5 versus 15 ± 5% CD45⁺; 1.3 ± 0.5 versus 1.8 ± 0.5% CD41⁺ cells). Also serial transplant experiments were performed with expanded and reselected CB cells. In secondary and tertiary recipients the Mk population was detected with bone marrow fluorescence-activated cell sorter analysis; these experiments indicate the effective long-term repopulation of expanded cells. Selected CD34⁺ cells after a 4-week expansion with FL+SCF+TPO are more efficient in Mk engraftment than the same number of unmanipulated cells.

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