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Partial reprogramming of heterologous cells by defined factors to generate megakaryocyte lineage-restricted biomolecules.

ABSTRACT: The ability of transcriptional regulators to drive lineage conversion of somatic cells offers great potential for the treatment of human disease. To explore the concept of switching on specific target genes in heterologous cells, we developed a model system to screen candidate factors for their ability to activate the archetypal megakaryocyte-specific chemokine platelet factor 4 (PF4) in fibroblasts. We found that co-expression of the transcriptional regulators GATA1 and FLI1 resulted in a significant increase in levels of PF4, which became magnified over time. This finding demonstrates that such combinations can be used to produce potentially beneficial chemokines in readily available heterologous cell types.

SUBMITTER: Artuz CM

PROVIDER: S-EPMC6197760 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Reprogramming of heterologous cells by defined factors to generate lineage-restricted biomolecules

Project description:The ability of transcriptional regulators to drive lineage conversion of somatic cells offers great potential for the treatment of human disease. While current research in this field is focused on the generation of induced pluripotent stem cells or direct lineage transdifferentiation, less attention has been paid to the possibility of reprogramming cells to produce cytokines, growth factors and hormones. To explore the concept of switching on specific target genes in heterologous cells, we developed a model system to screen candidate factors for their ability to activate the archetypal megakaryocyte-specific chemokine platelet factor 4 (PF4) in fibroblasts. We found that co-expression of the transcriptional regulators GATA1 and FLI1 resulted in a significant increase in levels of PF4, which became magnified over time. We also determined that inclusion of a third factor, TAL1, further enhanced upregulation of PF4 expression. Our study therefore identified of TAL1 as an important component in the combination of transcriptional regulators that contribute to megakaryocyte programming, and demonstrated that such combinations can be used to produce potentially beneficial chemokines in readily available heterologous cell types.

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