The Surprisingly Simple Recipe for Starting to Grow a Limb

Good news!

"At a glance:

1. In a first, scientists have identified the proteins needed to kick-start limb formation in mice and chicks.
2. The findings allow researchers for the first time to turn non-limb-forming cells into limb-forming ones and keep them alive in the lab for far longer than once possible.
3. Work deepens understanding of early limb development and could contribute to the long-term goal of regenerating limbs lost to injury and disease.

...

The team found that a combination of just three proteins — Prdm16, Zbtb16, and Lin28a — is necessary and sufficient to turn certain non-limb-forming stem cells into limb-forming ones. A fourth protein, Lin41, speeds the process along.

Part of a family called gene transcription factors, these proteins activate a handful of genes inside certain cells in embryonic tissue known as mesenchyme, the researchers revealed. This change in gene activity is what transforms the cells into limb progenitor cells, the team showed. ..."

From the highlights and abstract:

"Highlights

• Established a primary 3D limb culture system that maintains early limb progenitor cells

• Used a reprogramming approach to identify factors imbuing a limb progenitor state

• Together, Prdm16, Zbtb16, and Lin28a can convert non-limb cells to limb progenitors

• Trajectory analysis identifies Lin41 as facilitating reprogramming by the other factors

Summary

The early limb bud consists of mesenchymal limb progenitors derived from the lateral plate mesoderm (LPM). The LPM also gives rise to the mesodermal components of the flank and neck. However, the cells at these other levels cannot produce the variety of cell types found in the limb. Taking advantage of a direct reprogramming approach, we find a set of factors (Prdm16, Zbtb16, and Lin28a) normally expressed in the early limb bud and capable of imparting limb progenitor-like properties to mouse non-limb fibroblasts. The reprogrammed cells show similar gene expression profiles and can differentiate into similar cell types as endogenous limb progenitors. The further addition of Lin41 potentiates the proliferation of the reprogrammed cells. These results suggest that these same four factors may play pivotal roles in the specification of endogenous limb progenitors."

The Surprisingly Simple Recipe for Starting to Grow a Limb | Harvard Medical School Study illuminates development, could inform limb regeneration efforts

Direct reprogramming of non-limb fibroblasts to cells with properties of limb progenitors (open access)

Graphical abstract