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Self-Renewal of Differentiated Cells – An “Enhancer” of Cell Therapies?

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Review of “Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells” from Science by Stuart P. Atkinson

At first glance, pluripotent stem cells and macrophages have little in common. However, there are hints that differentiated macrophages can in fact maintain themselves via self-renewal mechanisms [1] and several studies have reported their expansion and maintenance over long-term in vitro culture [2-4]. Researchers from the laboratories of Arend Sidow and Michael H. Sieweke sought to understand the regulatory mechanisms which enable differentiated cells to self-renew and they now report their interesting findings in Science [5].

The study centered its focus on enhancer elements; regulatory regions of DNA generally marked by monomethylated histone H3 at Lysine 4 (H3K4me1) which are known to provide a reliable signature of cell identity [6]. Assessment of enhancer regions in either quiescent or self-renewing macrophages [3] when compared to other cell types with extended self-renewal capacity found no common pattern of shared enhancer positions that may control self-renewal. However, when they looked for the sign of activated enhancers [p300 (histone acetyl transferase) binding and acetylation of histone 3 lysine 27 (H3K27ac)], they found a large number of enhancers specifically activated in self-renewing macrophages.

When concentrating on the genes associated with these enhancers, the researchers came across an interesting result; they found an expression pattern associated with the transcriptional signature of embryonic stem cells (ESCs). This 16 self-renewal-associated gene pattern included KLF4, MYC, DPPA3, and several chromatin-associated proteins (EED, SUZ12, and CHD1). However, although the same genes were activated, ESCs and macrophages actually used distinct enhancer elements to aid in activating gene expression.

So what mechanisms control the movement of macrophages from quiescence to self-renewal and back? Analysis of the macrophage enhancer elements demonstrated that the transcription factor MafB bound and repressed self-renewal enhancers while assessment of alveolar macrophages found that naturally low levels of MafB and cMaf led to the activation of the same enhancers.

This study describes, through the use of alternative enhancer regions, just how differentiated cells such as macrophages can self-renew. But is there more to this research? Could we co-opt these enhancer elements to renew other differentiated cells and so provide a means to extend their functional lifespan, stop a variety of age-related disorders, and even, perhaps, extend overall lifespan? Perhaps a more readily graspable plan may be to study if we can use these enhancers to improve the generation of induced pluripotent stem cells (iPSCs) from which we may be able to generate better therapeutic strategies.

References

  1. Sieweke MH and Allen JE Beyond stem cells: self-renewal of differentiated macrophages. Science 2013;342:1242974.
  2. Gautier EL, Shay T, Miller J, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 2012;13:1118-1128.
  3. Aziz A, Soucie E, Sarrazin S, et al. MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. Science 2009;326:867-871.
  4. Fejer G, Wegner MD, Gyory I, et al. Nontransformed, GM-CSF-dependent macrophage lines are a unique model to study tissue macrophage functions. Proc Natl Acad Sci U S A 2013;110:E2191-2198.
  5. Soucie EL, Weng Z, Geirsdottir L, et al. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells. Science 2016;351:aad5510.
  6. Heintzman ND, Hon GC, Hawkins RD, et al. Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 2009;459:108-112.