Diverse reprogramming induces connective-tissue cells to adopt a neuron-like identity in culture

In humans and other mammals, the BRAIN contains hundreds of subtypes of nerve cells (neurons) –– each defined by a specific combination of features, including position within the brain, shape, neurotransmitter molecules that are produced, and electrophysi­ological properties. Attempting to understand this enor­mous diversity, and to create this in the laboratory cell culture dish, are ultimate goals of regenerative medicine. The [attached] article and editorial describe a large-scale screening effort to identify factors that can provide non-neural cells, cultured in a dish, with the capacity to take on “neuronal properties”.

Work over the past three decades has discovered gene regulatory networks that control neuronal identity –– as it unfolds in embryonic brain. These studies have also revealed how genes that induce neuronal identity are intimately linked to the environment in which neurons develop. Hence, we see the connection to these GEITP pages, i.e. gene-environment interactions. 🙂

Some of the nerve cells’ most important features –– such as their neural connections –– depend on their interac­tions with other neurons. Recently, it has become clear that many neuronal attributes can be generated outside the normal context of brain development. For example, it was discovered that a cocktail of three transcription factors can be applied to fibroblasts (the most common cell type present in connective tissue) in cell cultures, in order to convert them into cells that resemble brain-derived neurons. This pro­cedure, called direct lineage reprogramming, is based on the premise that certain transcrip­tion factors regulate gene-expression patterns characteristic of neuronal cell types. But what has not been clear is whether the capacity to reprogram cells into neurons is limited to a few, or many, transcription factors.

Previous work by the group that published this current study [attached] demonstrated that a pair of tran­scription factors from the basic helix-loop-helix (bHLH) and Pit-Oct-Unc (POU) families can induce expression of neuronal markers through direct reprogramming. Therefore, authors [attached] screened 598 pairs of bHLH and POU transcription factors — chosen on the basis of their expression in neu­ronal lineages — to see which might be able to transform mouse embryonic fibroblasts into neurons.

Amazingly, it was not “just a few”, but rather (and this is mind-boggling) –– they found 76 of these transcription-factor pairs –– were able to pro­duce cells that expressed multiple markers of mature neurons and exhibited neuronal morpholo­gies..!! Thus, neuronal features can be induced in non-neuronal cells by an astonishing range of transcription-factor combinations.

Nature 17 May 2o18; 557: 375–380 [full article] & pp 316–317 [News-N-Views]

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