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Induced Erythroid Progenitors – A New Means to Produce Mature RBCs?

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Review of “Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion” from Cell Reports by Stuart P. Atkinson

The production of red blood cells (RBCs) from erythroid progenitors in vitro may provide a means to match supply to the demand for transfusions of common and rare blood types. The direct conversion of patient fibroblasts to induced erythroid progenitors represents one potentially exciting strategy to achieve heightened supply, although we still do not understand the factors that make up the core erythroid transcriptional machinery.

In a new Cell Reports study, researchers from the laboratory of Johan Flygare have identified a group of 4 transcription factors with the ability to faithful convert mouse and human fibroblasts into induced erythroid progenitors (iEPs) from which RBCs can be produced [1]. They hope that their new system will find use as a model for both normal erythroid development and disease and as a means to produce mature RBCs at the large scale [2].

Initial experiments assayed 63 candidate pro-erythrogenic factors for their ability to reprogram adult tail tip fibroblasts (TTFs) derived from erythroid lineage-tracing mice [3]. This first pass identified seven transcription factors whose co-expression mediated the conversion of TTFs into cells with an erythroid precursor-like morphology in 8 days. Further tweaking whittled the list of seven down to four (Gata1, Tal1, Lmo2, or c-Myc; or GTLM), which the authors presented as the minimal set of factors required for the formation of induced erythroid precursors (iEP).
Transcriptional analysis of iEPs uncovered the expected downregulation fibroblast-specific gene expression and the upregulation of erythroid cell-specific gene expression, and, overall, demonstrated a striking resemblance of iEPs with bona fide burst-forming unit-erythroid colony cells.

However, embryonic globin expression predominated over adult globin expression, so suggesting that reprogramming induced a primitive, rather than definitive, erythroid program. Assessment of iEPs differentiation capacity employing the colony-forming assay found further proof of immaturity, as the colonies of red cells produced presented gene expression profiles similar to primitive erythroblasts.

As a remedy to this immaturity, which stands as a major obstacle for the clinical application of stem cell-derived RBCs [4], the authors co-expressed factors known to downregulate the expression of embryonic and fetal globin genes alongside GTLM. While they observed some success with Klf1 and Myb, this was not sufficient to fully switch from a primitive to a definitive gene expression program.

The identification of the core set of factors needed to “kick-start” the erythroid transcriptional program in mouse non-hematopoietic, differentiated somatic cells will hopefully lead to the future production of pure and fully mature RBCs. Encouragingly, the authors also demonstrated some success with generating human induced erythroid progenitors from human fibroblasts and the human versions of GTLM, suggestive of the conservation of the erythroid transcriptional program. Will we see in vitro produced blood products reach the market anytime soon? Keep an eye on the Stem Cells Portal to keep yourself informed!

References

1. Capellera-Garcia S, Pulecio J, Dhulipala K, et al. Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion. Cell Rep 2016;15:2550-2562.
2. Tsiftsoglou AS, Vizirianakis IS, and Strouboulis J Erythropoiesis: model systems, molecular regulators, and developmental programs. IUBMB Life 2009;61:800-830.
3. Heinrich AC, Pelanda R, and Klingmuller U A mouse model for visualization and conditional mutations in the erythroid lineage. Blood 2004;104:659-666.
4. Anstee DJ, Gampel A, and Toye AM Ex-vivo generation of human red cells for transfusion. Curr Opin Hematol 2012;19:163-169.