Transforming skin cells into limb cells lays groundwork for regenerative therapy

The findings published in the Journal Developmental Cell enhanced the understanding of limb development and laid the groundwork for regenerative therapy in the future.

Approximately 60 million individuals worldwide are living with limb loss, a consequence of diverse medical issues like tumours, infections, birth defects, or trauma from accidents, as well as natural disasters. Those with limb injuries often resort to synthetic materials and metal prostheses for support. However, numerous researchers are delving into the intricacies of limb development, striving to advance regenerative therapy or natural tissue replacement as a promising treatment option.

“During limb development in the embryo, limb progenitor cells in the limb bud give rise to most of the different limb tissues, such as bone, muscle, cartilage and tendon. It’s therefore important to establish an easy and accessible way of making these cells,” explained Dr. Yuji Atsuta, lead researcher at The Harvard Medical School.

Currently, limb progenitor cells are commonly sourced from embryos, posing ethical dilemmas with human embryos. Alternatively, induced pluripotent stem cells, reprogrammed from adult cells, can be utilized, but they carry risks of cancerous transformation. The new method developed by Atsuta and colleagues, which directly reprograms fibroblast cells into limb progenitor cells and bypasses induced pluripotent stem cells, simplifies the process and reduces costs. It also mitigates the concern of cells turning cancerous, which often occurs with induced pluripotent stem cells.

In the initial phase, researchers examined gene expression in early limb buds of mice and chicken embryos. They found 18 genes, mostly transcription factors, highly expressed in limb buds. Introducing these genes into fibroblasts from mouse embryos led to the cells resembling limb progenitor cells in gene expression. Further experiments identified three essential proteins—Prdm16, Zbtb16, and Lin28a—to reprogram fibroblasts into limb progenitor-like cells, with Lin41 aiding in cell growth and multiplication.

“These reprogrammed cells are not only molecular mimics; we have confirmed their potential to develop into specialized limb tissues, both in laboratory dishes (in vitro) and also in living organisms (in vivo),” said Atsuta. “Testing in vivo was particularly challenging, as we had to transplant the reprogrammed mouse cells into the limb buds of chicken embryos.”

Reference: Yuji Atsuta 8, ChangHee Lee 8, Alan R. Rodrigues 8, Charlotte Colle, Reiko R. Tomizawa, Ernesto G. Lujan,Patrick Tschopp, Laura Galan, Meng Zhu, Joshua M. Gorham, Jean-Pierre Vannier, Christine E. Seidman, Jonathan G. Seidman, Marian A. Ros, Olivier Pourquié, Clifford J. Tabin 9; JOURNAL: Developmental Cell; DOI: 10.1016/j.devcel.2023.12.010