MACROMOLECULAR CROWDING INCREASES HUMAN BONE MARROW-DERIVED MESENCHYMAL STEM CELL PROLIFERATION VIA ENHANCED GROWTH FACTOR SIGNALLING

Abstract

HUMAN BONE MARROW-DERIVED MESENCHYMAL STEM CELLS (HMSCS) HAVE ALWAYS BEEN HIGHLY REGARDED DUE TO THEIR GREAT THERAPEUTIC POTENTIAL. UNFORTUNATELY, HMSCS EXIST IN LOW OCCURRENCES OF 0.001 - 0.01% IN BONE MARROW ASPIRATES AND EXPANSION IS ESSENTIAL TO ATTAIN CLINICALLY RELEVANT NUMBERS. HERE, WE INTRODUCED MACROMOLECULAR CROWDING; A BIOPHYSICAL CONCEPT THAT ATTEMPTS TO MIMIC THE IN VIVO STEM CELL MICROENVIRONMENT AT RELEVANT FRACTIONAL VOLUME OCCUPANCY AND SHOWED THAT HMSC PROPAGATION WITH MMC ACHIEVED 12.5-FOLD MORE CELLS THAN CORRESPONDING CONTROLS UP TO 7 CONSECUTIVE PASSAGES. NOT ONLY DO THESE CELLS ADHERE TO ISCT MINIMAL CRITERIA, THEY EXPRESS NORMAL KARYOTYPE AND MAINTAIN THEIR TELOMERE LENGTHS. THE PROLIFERATIVE BOOST RESULTED FROM A PLEOTROPIC INCREASE IN SIGNALLING OF VARIOUS MITOGENIC GROWTH FACTORS FROM THE ENHANCED MICROENVIRONMENT UNDER MMC. THUS, THE USE OF MMC IN HMSC EXPANSION COULD POTENTIALLY ALTER THE BOTTLENECK OF AN INSUFFICIENT SUPPLY OF QUALITY HMSCS FOR ALLOGENEIC