“Well there goes another couple of thousand brain cells…” – a common thought after a beer, a glass of wine, or an hour or so of television, or maybe more if it’s reality TV. But can we replace these lost cells? Millions of college kids would like to, but there’s also a long list of applied research fields that could benefit from renewable sources of neural cells including cell replacement therapy, disease modeling, and drug testing.
Direct reprogramming, or transdifferentiation, uses the overexpression of specific transcription factors (TFs) to induce the conversion of one somatic cell into another cell type. Many groups have attempted to generate induced neural stem cells (iNSCs) for expansion and differentiation to generate a clinically relevant number of mature neural cells. These efforts have been only partly successful; generated iNSCs required continued TF expression to keep them in a stable NSC-like state, which inhibits their expansion and differentiation capabilities.
Now, researchers from the always inventive laboratory of Rudolf Jaenisch have developed an alternative strategy to generate stable iNSCs from various somatic cell types. Resultant cells resemble endogenous brain-derived NSCs at the transcriptional and epigenetic level and their differentiation capacity remains following long-term culture, all without the need for exogenous TF expression.
So how did they do it?
The group combined growth conditions designed to promote NSC growth with drug-induced expression of NSC-specific TFs in mouse embryonic fibroblasts (MEFs).
After a minimum of 30 days of transcription factor expression, the authors saw a few interesting things:
- Derived iNSCs resembled control brain-derived NSCs with regards to size, shape, and gene expression
- iNSCs displayed multipotentiality – they could differentiate into functional neurons, astrocytes and oligodendrocytes
- These characteristics remained in long term culture even after the removal of the drug which maintains exogenous TF expression
- Microarray gene expression analysis and ChIP-Seq analysis of gene enhancer acetylation demonstrated a striking similarity between iNSCs and control NSCs, suggesting stable transdifferentiation
The team also went on to derive iNSCs from mature liver cells and B lymphocytes, and in doing so, proved that iNSC generation from varying somatic cell sources is possible. MEF cultures can contain neural cell types (neural crest-derived cells) so it was important to assess if transdifferentiation was possible from cells of differing origins.
The next step is to move from mouse cells to human cells; easy to say, but perhaps harder to do. Let’s hope that this strategy proves to be transferrable as the implications are obvious to human health. In the meantime, put some of your fully functional neural cells to work, read this fascinating study here.