Preprint: old connective tissue cells disrupt orientation in young cells through the protein ApoD

Preprint: old connective tissue cells disrupt orientation in young cells through the protein ApoD

A bioRxiv preprint dated September 10 describes a feedback loop: ApoD, a protein secreted by old fibroblasts, which are connective tissue cells, increases SUN1 levels at the nuclear envelope and disrupts the orientation of young cells. High SUN1 levels increased ApoD production. In a mouse model, daily intravenous injections of ApoD impaired recovery from muscle injury.

Before moving, a fibroblast establishes its front and rear: the nucleus and the centrosome, the structure from which microtubules extend, move into position. This organization is called cell polarity. The authors exposed young fibroblasts to culture medium in which old cells had grown. After a signal to move, the young cells were less able to position their nucleus and centrosome correctly; medium from young fibroblasts did not have this effect.

Analysis of the proteins in the medium identified apolipoprotein D (ApoD) as a candidate. Purified ApoD caused the same defect. In young fibroblasts, it increased the level of SUN1, a protein in the inner nuclear membrane. SUN1 and nesprin-2, a protein that spans the membrane, link the nucleus to microtubules, which are protein filaments inside the cell. When SUN1 levels were high, this connection prevented the nucleus from moving into the correct position. Suppressing SUN1 or disrupting the connection between microtubules and the nucleus eliminated the effect of ApoD on cell polarity.

High SUN1 levels also increased ApoD production and secretion, while suppressing SUN1 reduced its secretion. Thus, ApoD increases SUN1 levels, and high SUN1 levels sustain further ApoD release. Through experiments involving nesprin-2, the authors linked this sequence to changes in gene activity, including that of Apod.

ApoD also increased SUN1 levels in muscle progenitor cells, the cells that give rise to muscle fibers, and impaired their ability to form fibers in culture. To test the effect in a living organism, the researchers administered ApoD to mice daily for ten days; on the fifth day, they induced a muscle injury in half the animals. Injured muscles in mice given ApoD had lower mass and contractile force than those in control animals; uninjured muscles showed no differences.