Cell isolation induces fate changes of bone marrow mesenchymal cells leading to loss or alternatively to acquisition of new differentiation potentials.
Mesenchymal stromal cell populations include a fraction, termed mesenchymal stem cells, exhibiting multipotency. Other cells within this population possess a lesser differentiation range. This was assumed to be due to a mesenchymal cellular cascade topped by a multipotent cell, which gives rise to progeny with diminishing differentiation potentials. Here, we show that mesenchymal cells, a priori exhibiting a limited differentiation potential, may gain new capacities and become multipotent following single-cell isolation. These fate changes were accompanied by upregulation of differentiation promoting genes, many of which also became H4K20me1 methylated. Early events in the process included TGFβ and Wnt modulation, and downregulation of hypoxia signaling. Indeed, hypoxic conditions inhibited the observed cell changes. Overall, cell isolation from neighboring partners caused major molecular changes and particularly, a newly established epigenetic state, ultimately leading to the acquisition of new differentiation potentials and an altered cell fate.
Department of Molecular Cell Biology, Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
Ofer
O
Shoshani
Orly
O
Ravid
Hassan
H
Massalha
Alla
A
Aharonov
Yossi
Y
Ovadya
Meirav
M
Pevsner-Fischer
Dena
D
Leshkowitz
Dov
D
Zipori
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D002999:Clone Cells / Q000166:cytology; D005434:Flow Cytometry; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
Adult stem cells; Cell signaling; Clonal assays; Epigenetics; Hypoxia; Marrow stromal cells; Reprogramming; Stem cell plasticity