Abstract
Background
Compelling evidence indicates that metformin, a low-cost and safe orally administered
biguanide prescribed to millions of type 2 diabetics worldwide, induces the osteoblastic
differentiation of mesenchymal stromal cells (MSCs) through the 5' adenosine monophosphate
(AMP)-activated protein kinase (AMPK) pathway. As a highly hydrophilic cationic compound,
metformin uptake is facilitated by cell membrane organic cation transporters (OCTs)
of the solute carrier 22A gene family. We hypothesized that to effectively enhance
osteogenic differentiation, and ultimately bone regeneration, metformin must gain
access into functional OCT-expressing MSCs.
Methods
Data was obtained through immunoblotting, cellular uptake, mineralization and gene
expression assays.
Results
We demonstrate for the first time that functional OCTs are expressed in human-derived
MSCs from umbilical cord Wharton's jelly, an inexhaustible source of nonembryonic
MSCs with proven osteogenic potential. A clinically relevant concentration of metformin
led to AMPK activation, enhanced mineralized nodule formation and increased expression
of the osteogenic transcription factor Runt-related transcription factor 2 (RUNX2).
Indeed, targeting OCT function through pharmacological and genetic approaches markedly
blunted these responses.
Conclusions
Our findings indicate that functional OCT expression in UC-MSCs is a biological prerequisite
that facilitates the intracellular uptake of metformin to induce an osteogenic effect.
Future pre-clinical studies are warranted to investigate whether the expression of
functional OCTs may serve as a potential biomarker to predict osteogenic responses
to metformin.
Key Words
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Article info
Publication history
Published online: March 16, 2018
Accepted:
February 11,
2018
Received:
December 12,
2017
Identification
Copyright
© 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
