Protein that protects nucleus also regulates stem cell differentiation

Aug. 29, 2013 The human body has hundreds of different cell types, all with the same basic DNA, and all of which can ultimately be traced back to identical stem cells. Despite this fundamental similarity, a bone cell has little in common with a brain cell when it comes to appearance or function. The fact that bone is rigid and mechanically distinct from soft fat or brain had been speculated to play some role in differentiation to new cells in those parts of the body, but mechanisms have been unclear.

Now, a study by researchers at the University of Pennsylvania have shown that a protein found in the nuclei of all cells -- lamin-A -- plays a key role in the differentiation process.

The study was led by professor Dennis Discher and postdoctoral researchers Joe Swift and Irena Ivanovska of the Department of Chemical and Biomolecular Engineering in Penn's School of Engineering and Applied Science.

It was published in the journal Science.

Lamin-A is a protein found in the nucleus of all adult cells. This rope-like protein forms a protective netting around the DNA contained at the core of the nucleus.

The first hint that lamin-A might be involved in regulating the stiffness of nuclei came from diseases that lead to abnormal protein. One such disease, progeria, has symptoms akin to premature aging, including brittle bones and muscle wasting. But while these stiff tissues are affected, soft tissues such as brain and blood remain normal.

As a self-assembling filament, lamin-A is like a rope in that, when it is pulled, it becomes taut. As this stiffness would be better suited to resisting the pull of neighboring cells, the researchers speculated that such a protein would be more abundant in tissues, like bone, cartilage and muscle, that need to be stiff to resist the stresses and strains of everyday activity.

"We hypothesized that higher levels of lamin-A in the nuclei of stiffer tissues would be appropriate to a greater need to prevent breakage of the precious DNA surrounded by the lamin-A net," Discher said.

To determine how levels of lamin-A varied between cell types, the researchers took tissue cells from both mice and humans, broke the cells apart and fed them to a mass spectrometer to quantify the many protein components.

The researchers then looked for any correlation between the amounts of the numerous proteins detected and the elasticity of the source tissue. Since the material outside cells called extracellular matrix is known to be particularly abundant in stiff tissues like bone and cartilage, they expected to see correlations with matrix proteins like collagen. However, they also found evidence supporting their hypothesis that nuclear lamin-A levels also increase dramatically from softer to more rigid tissues.

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Protein that protects nucleus also regulates stem cell differentiation