Human multipotent stromal cells from bone marrow and microRNA: regulation of differentiation and leukemia inhibitory factor expression.
We observed that microRNAs (miRNAs) that regulate differentiation in a variety of simpler systems also regulate differentiation of human multipotent stromal cells (hMSCs) from bone marrow. Differentiation of hMSCs into osteoblasts and adipocytes was inhibited by using lentiviruses expressing shRNAs to decrease expression of Dicer and Drosha, two enzymes that process early transcripts to miRNA. Expression analysis of miRNAs during hMSC differentiation identified 19 miRNAs that were up-regulated during osteogenic differentiation and 20 during adipogenic differentiation, 11 of which were commonly up-regulated in both osteogenic and adipogenic differentiation. In silico models predicted that five of the up-regulated miRNAs targeted leukemia inhibitory factor (LIF) expression. The prediction was confirmed for two of the miRNAs, hsa-mir 199a and hsa-mir346, in that over-expression of the miRNAs decreased LIF secretion by hMSCs. The results demonstrate that differentiation of hMSCs is regulated by miRNAs and that several of these miRNAs target LIF.
Oskowitz
Adam Z
AZ
Center for Gene Therapy and Department of Pharmacology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Lu
Jun
J
Penfornis
Patrice
P
Ylostalo
Joni
J
McBride
Jane
J
Flemington
Erik K
EK
Prockop
Darwin J
DJ
Pochampally
Radhika
R
D000273:Adipose Tissue / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000378:metabolism*; D035683:MicroRNAs / Q000502:physiology*; D039902:Multipotent Stem Cells / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology*
D053605:Leukemia Inhibitory Factor; D035683:MicroRNAs; D012333:RNA, Messenger; C517918:DROSHA protein, human; D043244:Ribonuclease III