“Fifth Element” Joins Classical iPSC Factors, Constrains Cell Death

Colonies of mouse iPSCs obtained in the presence of netrin-1. Top, in white light. Bottom, labeled with pluripotency factor Oct4. [©Inserm/Fabrice Lavial]

The factors used to induce pluripotency and create so-called adult stem cells are anything but inert, but they could use extra “oomph.” To enhance their effect, say scientist in France, introduce another factor, a naturally occurring protein called netrin-1. With netrin-1, the original factors—Oct4, Sox2, Klf4, and c-Myc—can produce many more induced pluripotent stems cells (iPSCs), mainly by limiting apoptosis, or cell death.

Netrin-1 has its effect somewhere downstream of the cell-reprogramming cascade initiated by the four well-known transcription factors. It emerged in a study of downstream factors that not only have a role in induced pluripotency, but also participate in programmed cell death.

This study, conducted by two teams of scientists (from Inserm, CNRS, Centre Léon Bérard and Claude Bernard Lyon 1 University), determined that the expression of netrin-1 is transiently suppressed during cell reprogramming. When these scientists add netrin-1 to compensate for its insufficiency in the early phases of reprogramming, they observed that the production of iPSCs was greatly enhanced.

The scientists presented their findings July 8 in Nature Communications, in an article entitled, “Netrin-1 regulates somatic cell reprogramming and pluripotency maintenance.” This article described how destabilization of the balance between netrin-1 and its receptor DCC (Deleted in Colorectal Carcinoma) leads to apoptosis induction at the early stage of reprogramming and reduces iPSC generation.

“In various somatic cells, we found that reprogramming is accompanied by a transient transcriptional repression of netrin-1 mediated by an Mbd3/Mta1/Chd4-containing NuRD complex,” wrote the authors. “Mechanistically, netrin-1 imbalance induces apoptosis mediated by the receptor DCC in a p53-independent manner. Correction of the netrin-1/DCC equilibrium constrains apoptosis and improves reprogramming efficiency.”

The study’s authors, led by Fabrice Lavial and Patrick Mehlen, asserted that netrin-1 can act as a recombinant protein to improve the generation of mouse and human iPSCs under specific culture conditions. They noted that their work also shed light on another metrin-1 function in embryonic stem cell self-renewal, notably by constraining UNC5b-mediated apoptosis.

From a therapeutic point of view, it was important to determine whether this treatment affected the quality of cell reprogramming.

“According to several verifications, netrin-1 treatment does not seem to have any impact on the genomic stability the iPS cells or on their ability to differentiate into other tissues,” said Fabrice Lavial, a research fellow at Inserm.

An Inserm-issued press release indicated that its scientists are continuing to test the effect of netrin-1 on the reprogramming of other types of cells, and are endeavoring to gain a better understanding of the mode of action of this molecule in stem cell physiology. The release also made a sly reference to “The Fifth Element,” a French science fiction film in which the protective powers of four mystical stones are unleashed by an elusive, yes, fifth element.