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Innate Immune Pathway Stimulation Enhances Reprogramming Strategies

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Review of “Retinoic Acid Inducible Gene 1 Protein (RIG1)-like Receptor Pathway is required for Efficient Nuclear Reprogramming” from STEM CELLS by Stuart P. Atkinson

Previous reprogramming studies from the laboratory of John P. Cooke (Houston Methodist Research Institute, Houston, Texas, USA) have established that while reprogramming factors themselves are vitally important, the retroviral vectors that deliver the factors may also contribute to the process [1]! Specifically, the team discovered that retroviral vectors stimulated the toll-like receptor 3 (TLR3) double-stranded RNA (dsRNA) sensing pathway of the innate immune system to promote the formation of an epigenetic state that enhances reprogramming.

Their new STEM CELLS study [2] now concentrates on another innate immune pathway stimulated by viral RNA; the retinoic acid-inducible gene 1-like receptor (RLR) pathway [3, 4]. Can modulation of this innate immune pathway help to generate efficient and effective reprogramming strategies?

The authors appraised the RLR pathway given that complete loss of TLR3 did not fully inhibit retroviral-mediated fibroblast reprogramming. Loss of interferon beta promoter stimulator 1 (IPS1), a protein required for RLR function, impaired reprogramming to a similar degree to TLR3 loss, while impairment of both RLR and TLR3 pathways reduced reprogramming efficiency even further (See Figure). 

In agreement with the author’s previous TLR3-based study, the addition of an RLR ligand to activate innate immunity enhanced iPSC colony number and pluripotent gene expression levels and this correlated with the appearance of permissive chromatin modifications (high H3K4me3/low H3K27me3) at pluripotency-associated gene promoters (e.g. Oct4 and Sox2).

Interestingly, the authors noted that innate immune activation also potentiated transdifferentiation [5], the direct reprogramming of fibroblasts into endothelial cells, in this case, so indicating an important role for innate immune pathways in other reprogramming events.

But why does the innate immune system prompt this response? The authors propose that the activation of innate immunity may increase permissive epigenetic modifications to induce a “phenotypically fluid” cellular state in order for the cell to respond quickly and effectively to pathogens or injury [6]. By artificially prompting this response in somatic cells, we may ease the access of reprogramming factors to their DNA binding sites and promote the acquisition of the pluripotent state. 

A great new study in an exciting area of reprogramming; keep up to date with all the cutting-edge findings here at the Stem Cells Portal.


  1. Lee J, Sayed N, Hunter A, et al. Activation of innate immunity is required for efficient nuclear reprogramming. Cell 2012;151:547-558.
  2. Sayed N, Ospino F, Himmati F, et al. Retinoic Acid Inducible Gene 1 Protein (RIG1)-Like Receptor Pathway Is Required for Efficient Nuclear Reprogramming. STEM CELLS 2017;35:1197-1207.
  3. Kato H, Sato S, Yoneyama M, et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 2005;23:19-28.
  4. Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol 2004;5:730-737.
  5. Sayed N, Wong WT, Ospino F, et al. Transdifferentiation of human fibroblasts to endothelial cells: role of innate immunity. Circulation 2015;131:300-309.
  6. Ghosh AK, Quaggin SE, and Vaughan DE. Molecular basis of organ fibrosis: potential therapeutic approaches. Exp Biol Med (Maywood) 2013;238:461-481.