ABSTRACT
To develop cell therapies for damaged nervous tissue with human neural stem/progenitor cells (hNPCs), the risk of an immune response and graft rejection must be considered. There are conflicting results and lack of knowledge concerning the immunocompetence of hNPCs of different origin. Here, we studied the immunogenicity and immunomodulatory potentials of hNPCs cultured under equivalent conditions after derivation from human embryonic stem cells (hESC-NPCs) or human fetal spinal cord tissue (hfNPCs). The expression patterns of human leukocyte antigen, co-stimulatory and adhesion molecules in hESC-NPCs and hfNPCs were relatively similar and mostly not affected by inflammatory cytokines. Unstimulated hfNPCs secreted more transforming growth factor-ß1 (TGF-ß1) and ß2 but similar level of interleukin (IL)-10 compared to hESC-NPCs. In contrast to hfNPCs, hESC-NPCs displayed 4-6 fold increases in TGF-ß1, TGF-ß2 and IL-10 under inflammatory conditions. Both hNPCs reduced the alloreaction between allogeneic peripheral blood mononuclear cells (PBMCs) and up-regulated CD4(+)CD25(+)forkhead box P3 (FOXP3)(+) T cells. However, hESC-NPCs but not hfNPCs dose-dependently triggered PBMC proliferation, which at least partly may be due to TGF-ß signaling. To conclude, hESC-NPCs and hfNPCs displayed similarities but also significant differences in their immunocompetence and interaction with allogeneic PBMCs, differences may be crucial for the outcome of cell therapy.
Subject(s)
Embryonic Stem Cells/cytology , Fetus/cytology , Neural Stem Cells/cytology , Spinal Cord/cytology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cell Proliferation , Cells, Cultured , Coculture Techniques , Embryonic Stem Cells/metabolism , Forkhead Transcription Factors/metabolism , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Humans , Interleukin-10/metabolism , Interleukin-2 Receptor alpha Subunit/metabolism , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Neural Stem Cells/immunology , Neural Stem Cells/metabolism , Spinal Cord/metabolism , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta2/metabolism , Up-RegulationABSTRACT
Human embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC) are an attractive cell source for regenerative medicine. These cells can be expanded to vast numbers and can be differentiated to many desired pluripotent stem cells (PSC) derived therapeutic cells. Cell replacement bears promises, but also challenges. The introduction of exogenous cells in a recipient must address several different topics; its safety, the exclusion of tumor formation, the immunological response and possible rejection, the cells cleanliness and their biological quality, and quantity representing the functionality of the PSC derived therapeutic cells. Tumor formation requires the removal of any PSC remaining after differentiation. Immunological rejection can be addressed with immunomodulation of the cells and the recipient. Cleanliness can be optimized using good manufacturing practice quality systems. At last, the functionality of the cells must be tested in in vitro and in animal models. After addressing these challenges, precise strategies are developed to monitor the status of the cells at different times and in case of undesired results, corresponding counteracting strategies must exist before any clinical attempt.
ABSTRACT
Neural stem cells have a broad differentiation repertoire during embryonic development and can be reprogrammed to pluripotency comparatively easily. We report that adult neural stem cells can be reprogrammed at very high efficiency to monocytes, a differentiated fate of an unrelated somatic lineage, by ectopic expression of the Ets transcription factor PU.1. The reprogrammed cells display a marker profile and functional characteristics of monocytes and integrate into tissues after transplantation. The failure to reprogram lineage-committed neural cells to monocytes with PU.1 suggests that neural stem cells are uniquely amenable to reprogramming.
