Defining the Minimal Factors Required for Erythropoiesis through Direct Lineage Conversion.
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.
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
Sandra
S
Capellera-Garcia
Center of Regenerative Medicine in Barcelona, Barcelona Biomedical Research Park, Doctor Aiguader 88, 08003 Barcelona, Spain.
Julian
J
Pulecio
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
Kishori
K
Dhulipala
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
Kavitha
K
Siva
The Rockefeller University, New York, NY 10065, USA.
Violeta
V
Rayon-Estrada
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
Sofie
S
Singbrant
Division of Molecular Hematology, BMC B12, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
Mikael N E
MN
Sommarin
St. Vincent's Institute of Medical Research and Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC 3065, Australia.
Carl R
CR
Walkley
Division of Molecular Hematology, BMC B12, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
Shamit
S
Soneji
Division of Molecular Hematology, BMC B12, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden.
Göran
G
Karlsson
Center of Regenerative Medicine in Barcelona, Barcelona Biomedical Research Park, Doctor Aiguader 88, 08003 Barcelona, Spain; Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain.
Ángel
Á
Raya
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
Vijay G
VG
Sankaran
Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: johan.flygare@med.lu.se.
Johan
J
Flygare
D000375:Aging; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D003114:Colony-Forming Units Assay; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005914:Globins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D014157:Transcription Factors / Q000378:metabolism*
D014157:Transcription Factors; D005914:Globins