Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion
Sandra Capellera-Garcia,
Julian Pulecio,
Kishori Dhulipala,
Kavitha Siva,
Violeta Rayon-Estrada,
Sofie Singbrant,
Mikael N.E. Sommarin,
Carl R. Walkley,
Shamit Soneji,
Göran Karlsson,
Ángel Raya,
Vijay G. Sankaran,
Johan Flygare
Affiliations
Sandra Capellera-Garcia
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Julian Pulecio
Center of Regenerative Medicine in Barcelona, Barcelona Biomedical Research Park, Doctor Aiguader 88, 08003 Barcelona, Spain
Kishori Dhulipala
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Kavitha Siva
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Violeta Rayon-Estrada
The Rockefeller University, New York, NY 10065, USA
Sofie Singbrant
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Mikael N.E. Sommarin
Division of Molecular Hematology, BMC B12, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Carl R. Walkley
St. Vincent’s Institute of Medical Research and Department of Medicine, St Vincent’s Hospital, University of Melbourne, Fitzroy, VIC 3065, Australia
Shamit Soneji
Division of Molecular Hematology, BMC B12, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Göran Karlsson
Division of Molecular Hematology, BMC B12, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Ángel Raya
Center of Regenerative Medicine in Barcelona, Barcelona Biomedical Research Park, Doctor Aiguader 88, 08003 Barcelona, Spain
Vijay G. Sankaran
Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
Johan Flygare
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden
Erythroid cell commitment and differentiation proceed through activation of a lineage-restricted transcriptional network orchestrated by a group of well characterized genes. However, the minimal set of factors necessary for instructing red blood cell (RBC) development remains undefined. We employed a screen for transcription factors allowing direct lineage reprograming from fibroblasts to induced erythroid progenitors/precursors (iEPs). We show that Gata1, Tal1, Lmo2, and c-Myc (GTLM) can rapidly convert murine and human fibroblasts directly to iEPs. The transcriptional signature of murine iEPs resembled mainly that of primitive erythroid progenitors in the yolk sac, whereas addition of Klf1 or Myb to the GTLM cocktail resulted in iEPs with a more adult-type globin expression pattern. Our results demonstrate that direct lineage conversion is a suitable platform for defining and studying the core factors inducing the different waves of erythroid development.
