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Slowly dividing follicle stem cells (green specks) are more abundant in mice lacking Zmpste24 (right).

Stem cells become sluggish in a disease that resembles premature aging, as Espada et al. show. The work is the first in vivo study to link the disease to stem cell abnormalities.

In some ways, children with Hutchinson-Gilford progeria syndrome (HGPS) resemble their grandparents. They lose their hair, their bones weaken, and they develop atherosclerosis, which usually kills them as teenagers. HGPS patients manufacture a defective version of lamin A, a key component of the nuclear lamina. Two years ago, Paola Scaffidi and Tom Misteli strengthened the link between aging and HGPS, showing that healthy people accumulate faulty lamin A at the edge of the nucleus as they age. One hypothesis suggests that mutant lamin A causes some infirmities of HGPS and aging by hampering stem cells.

Espada et al. tested this idea using a mouse model of HGPS. The animals fashion faulty lamin A because they lack an enzyme, Zmpste24, that helps trim the protein into its functional form. The team first measured the abundance of the skin's follicle stem cells, which promote wound healing and hair growth. To the researchers' surprise, the Zmpste24-deficient mice harbored more of these stem cells than did controls. However, these more numerous cells were reluctant to divide. In culture, stem cells from the mutant mice spawned smaller colonies than did cells from normal animals.

The researchers also found that abnormal lamin A disrupts the Wnt/β-catenin pathway that helps control the proliferation of stem cells. Zmpste24-lacking mice contained less of the active form of β-catenin and less cyclin D1, one of the division-promoting targets of the pathway.

Last month, Scaffidi and Misteli reported that mutant lamin A disrupted differentiation of mesenchymal stem cells (Scaffidi, P., and T. Misteli. Nat. Cell Biol. doi:10.1038/ncb1708). However, Espada et al. found that the follicle stem cells differentiated normally.

The mutant mice didn't show increased apoptosis by stem cells. But the suicide rate was higher among neighboring cells, whose signals nudge the stem cells to divide. The researchers conclude that abnormal lamin disrupts not just stem cells but also the surrounding cells that help control their behavior. The next step, the researchers say, is to look for similar defects in other stem cell types, such as hematopoietic stem cells.

Reference:

Espada, J., et al. 2008. J. Cell Biol. 181:27–35.[Abstract/Free Full Text]

Mitch Leslie

mitchleslie{at}comcast.net

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This Article PDF (Full Text) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Leslie, M. PubMed Articles by Leslie, M. Social Bookmarking                      What's this?