The HOXB4 homeoprotein promotes the ex vivo enrichment of functional human embryonic stem cell-derived NK cells

• Published in: PloS one 2012-06, Vol.7 (6), p.e39514-e39514
• Main Authors: Larbi, Aniya, Gombert, Jean-Marc, Auvray, Céline, l'Homme, Bruno, Magniez, Aurélie, Féraud, Olivier, Coulombel, Laure, Chapel, Alain, Mitjavila-Garcia, Maria Teresa, Turhan, Ali G, Haddad, Rima, Bennaceur-Griscelli, Annelise
• Format: Article
• Language: English
• Subjects: Anemia; Biology; Blood; Blood cells; Cancer therapies; CD34 antigen; CD45RA antigen; Cell culture; Cell Differentiation - physiology; Cell Line; Cells (biology); Coculture Techniques; Cytokines; Cytotoxicity; Dendritic cells; Embryo cells; Embryonic stem cells; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Enrichment; Gene expression; Genes; Hematopoietic stem cells; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; HOXB4 protein; Humans; Immunoglobulins; Killer cells; Killer Cells, Natural - cytology; Killer Cells, Natural - metabolism; Laboratories; Leukemia; Life Sciences; Medicine; Pluripotency; Proteins; Stem cells; Stromal cells; Stromal Cells - cytology; Stromal Cells - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor necrosis factor-TNF; Umbilical cord; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039514

Human embryonic stem cells (hESCs) can be induced to differentiate into blood cells using either co-culture with stromal cells or following human embryoid bodies (hEBs) formation. It is now well established that the HOXB4 homeoprotein promotes the expansion of human adult hematopoietic stem cells (HSCs) but also myeloid and lymphoid progenitors. However, the role of HOXB4 in the development of hematopoietic cells from hESCs and particularly in the generation of hESC-derived NK-progenitor cells remains elusive. Based on the ability of HOXB4 to passively enter hematopoietic cells in a system that comprises a co-culture with the MS-5/SP-HOXB4 stromal cells, we provide evidence that HOXB4 delivery promotes the enrichment of hEB-derived precursors that could differentiate into fully mature and functional NK. These hEB-derived NK cells enriched by HOXB4 were characterized according to their CMH class I receptor expression, their cytotoxic arsenal, their expression of IFNγ and CD107a after stimulation and their lytic activity. Furthermore our study provides new insights into the gene expression profile of hEB-derived cells exposed to HOXB4 and shows the emergence of CD34(+)CD45RA(+) precursors from hEBs indicating the lymphoid specification of hESC-derived hematopoietic precursors. Altogether, our results outline the effects of HOXB4 in combination with stromal cells in the development of NK cells from hESCs and suggest the potential use of HOXB4 protein for NK-cell enrichment from pluripotent stem cells.