Direct reprogramming of non-limb fibroblasts to cells with properties of limb progenitors

Yuji Atsuta; ChangHee Lee; Alan R Rodrigues; 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

doi:10.1016/j.devcel.2023.12.010

Direct reprogramming of non-limb fibroblasts to cells with properties of limb progenitors

Dev Cell. 2024 Feb 5;59(3):415-430.e8. doi: 10.1016/j.devcel.2023.12.010.

Authors

Yuji Atsuta¹, ChangHee Lee², Alan R Rodrigues³, Charlotte Colle⁴, Reiko R Tomizawa⁴, Ernesto G Lujan⁵, Patrick Tschopp⁶, Laura Galan⁷, Meng Zhu⁴, Joshua M Gorham⁴, Jean-Pierre Vannier⁸, Christine E Seidman⁴, Jonathan G Seidman⁴, Marian A Ros⁷, Olivier Pourquié⁹, Clifford J Tabin¹⁰

Affiliations

¹ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Department of Biology, Kyushu University, Fukuoka 819-0395, Japan.
² Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: chlee@genetics.med.harvard.edu.
³ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
⁴ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
⁵ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA.
⁶ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Zoological Institute, University of Basel, 4051 Basel, Switzerland.
⁷ Instituto de Biomedicina y Biotecnologia de Cantabria, CSIC, SODERCAN- Universidad de Cantabria, 39011 Santander, Spain.
⁸ Unité Inserm U1234/Université de Rouen, IRIB, 76183 Rouen Cedex, France.
⁹ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA 02115, USA. Electronic address: pourquie@genetics.med.harvard.edu.
¹⁰ Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: tabin@genetics.med.harvard.edu.

PMID: 38320485
PMCID: PMC10932627 (available on 2025-02-05)
DOI: 10.1016/j.devcel.2023.12.010

Abstract

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.

Keywords: Lin28a; Lin41; Pdrm16; Zbtb16; lateral plate mesoderm; limb bud; limb culture; limb progenitors; reprogramming.

MeSH terms

Animals
Extremities*
Fibroblasts
Limb Buds
Mesoderm / metabolism
Mice
Proteins* / metabolism

Substances

Proteins

Grants and funding

R01 HD032443/HD/NICHD NIH HHS/United States