Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors.
Recent studies implicated the existence of adult lymphoid-primed multipotent progenitors (LMPPs) with little or no megakaryocyte-erythroid potential, questioning common myeloid and lymphoid progenitors as obligate intermediates in hematopoietic stem cell (HSC) lineage commitment. However, the existence of LMPPs remains contentious. Herein, global and single-cell analyses revealed a hierarchical organization of transcriptional lineage programs, with downregulation of megakaryocyte-erythroid genes from HSCs to LMPPs, sustained granulocyte-monocyte priming, and upregulation of common lymphoid (but not B and T cell-specific) genes. These biological and molecular relationships, implicating almost mutual exclusion of megakaryocyte-erythroid and lymphoid pathways, are established already in fetal hematopoiesis, as evidenced by existence of LMPPs in fetal liver. The identification of LMPPs and hierarchically ordered transcriptional activation and downregulation of distinct lineage programs is compatible with a model for HSC lineage commitment in which the probability for undergoing different lineage commitment fates changes gradually when progressing from HSCs to LMPPs.
Månsson
Robert
R
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, 221 84 Lund, Sweden.
Hultquist
Anne
A
Luc
Sidinh
S
Yang
Liping
L
Anderson
Kristina
K
Kharazi
Shabnam
S
Al-Hashmi
Suleiman
S
Liuba
Karina
K
Thorén
Lina
L
Adolfsson
Jörgen
J
Buza-Vidas
Natalija
N
Qian
Hong
H
Soneji
Shamit
S
Enver
Tariq
T
Sigvardsson
Mikael
M
Jacobsen
Sten Eirik W
SE
D053687:Adult Stem Cells / Q000166:cytology / Q000276:immunology*; D000818:Animals; D019070:Cell Lineage / Q000235:genetics*; D047109:Fetal Development / Q000235:genetics; D005333:Fetus / Q000166:cytology / Q000276:immunology*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology*; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology / Q000276:immunology*; D014158:Transcription, Genetic