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. 2021 Jul 21;12:714822. doi: 10.3389/fimmu.2021.714822

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Copyright © 2021 Zimmermannova, Caiado, Ferreira and Pereira

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Cell reprogramming as a source of immune cells. Cellular reprogramming provides an opportunity to generate tailored immune cells for immunotherapy. Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) with the transcription factors OCT4, SOX2, KLF4, and c-MYC. iPSCs are then differentiated to hematopoietic progenitor cells (HPCs) with the cytokines stem cell factor (SCF), vascular endothelial growth factor (VEGF), and bone morphogenetic protein 4 (BMP4). Protocols for the differentiation of HPCs into myeloid and lymphoid lineages involve exposing cells to complex cytokine cocktails and/or feeder layers including MS-5, OP9-DL1, or artificial thymic organoids (ATO) supporting lymphopoiesis. Due to the self-renewal capacity of pluripotent stem cells, iPSC reprogramming (top panel) can generate immune cells on a large scale and is suitable for ex vivo genome editing. Cells undergo rejuvenation and erasure of epigenetic marks associated with aging or exhaustion. However, iPSC differentiation into mature immune cells is challenging (dashed lines) and leads to the generation of heterogeneous populations. Direct reprogramming (also known as transdifferentiation, bottom panel) refers to a change in cell fate mediated by lineage transcription factors that, unlike in iPSC reprogramming, does not involve pluripotent intermediates. The direct reprogramming of fibroblasts to macrophages (MØ) or conventional dendritic cells type 1 (cDC1) induce exclusively the target immune cell fate. Direct reprogramming is a faster and more efficient process. It can be elicited both in vitro and within the target tissue, thus having potential for in vivo reprogramming. It also reduces tumorigenic risks from contaminating stem cells. Moreover, direct reprogramming may retain epigenetic aging hallmarks, making it more suitable for modeling aging-related disease but more difficult to achieve complete epigenetic reprogramming. Transcription factors can also be applied to accelerate and direct the differentiation of iPSCs (also known as forward reprogramming, top panel). FLT3L, Fms-like tyrosine kinase 3 ligand; TPO, Thrombopoietin; IL, interleukin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; cDC2, conventional dendritic cells type 2 DCs; pDCs, plasmacytoid DCs; NK, natural killer; ILCs, innate lymphoid cells.