Journal Club: Regenerative Medicine, Neuroscience, Biochemistry, and Stem Cell Biology

Graduate Division

REGENERATIVE MEDICINE: Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages. Li, K., et al. (Ding). Cell Stem Cell. 2014. 14(2):228-236.

For nearly a century, insulin therapy has allowed those with Type 1 diabetes to live long lives, albeit through frequent monitoring and treatment and with heightened risks of a variety of health problems. Pursuit of a practical, permanent cure continues.

In the past decade, groups have differentiated insulin-producing pancreatic β cells from induced pluripotent stem cells and directly from hepatocytes and a few other cell types. However, no group had developed a general method for direct differentiation of non-endodermal cells into β cells, which might be useful for reliably and safely producing large numbers of them.

In this article, the authors show that they have directly reprogrammed mouse fibroblasts into definitive endoderm-like cells and then used several small molecules to further develop these into pancreatic-progenitor-like cells. When transplanted into mice, these cells developed into β-like cells that made enough insulin to control blood sugar.

NEUROSCIENCE: Phonetic feature encoding in human superior temporal gyrus. Mesgarani, N., et al. (Chang). Science. 2014 Jan. 30. Epub ahead of print.

The smallest meaningful speech sounds are called phonemes: such as the difference between pat and bat. The superior temporal gyrus of the brain has previously been found to be important in processing speech, but the way in which speech sounds are mapped to this region was unclear.

In this paper, Mesgarani and colleagues report on their study of six subjects implanted with multi-electrode arrays as part of clinical examination of their epilepsy. Researchers observed the subject's patterns of brain activity as they listened to a large number of sentences that included all the phonemes in American English.

The researchers found that rather than each phoneme having its own brain region, there were different regions for different phonetic features, such that one region was activated by sounds such as s and z and another by sounds such as p, b, and d.   

BIOCHEMISTRY: An allosteric Sec61 inhibitor traps nascent transmembrane helices at the lateral gate. MacKinnon, A.L., et al. (Taunton). eLife. 2014. 3:e01483

Membrane proteins in eukaryotes are typically integrated into the membrane of the endoplasmic reticulum as they are translated. Their entry is facilitated by a translocation channel that includes Sec61.

Although it has long been known that the Sec61 channel laterally directs the new protein's transmembrane domain into the membrane, the exact way in which this occurs has remained hazy.

The authors here present new insights into this process obtained using a selective Sec61 inhibitor, which they found to likely bind near the lumenal plug. Before exiting the channel, the transmembrane domain interacts with Sec61 near the cytosolic tip of the lateral gate, resulting in shifts in this gate that permit the transmembrane domain to integrate into the membrane.

STEM CELL BIOLOGY: Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. Pietras, E.M., et al. (Passegué). J Exp Med. 2014 Feb. 3. Epub ahead of print.

In the time it takes to read this sentence, your body will produce several million red blood cells, a process ultimately dependent on hematopoietic stem cells (HSCs). Most of the time, however, a given HSC is quiescent: not actively dividing.

Type I interferons are a family of cytokines associated with antiviral responses and used in treating select infections and blood cancers. Previous research found they tend to depress production of blood cells but do not kill HSCs, in fact appearing to induce greater HSC proliferation.

In this paper, the authors clarified this somewhat confusing situation. They found that although initially exposure to type I interferon causes HSCs to proliferate, they soon return to quiescence. They then remain safe from the cytotoxic effects of chronic interferon unless forced into the cell cycle, at which point they die in a p53-dependent manner.