RESISTANCE OF UNDIFFERENTIATED MESENCHYMAL STEM CELLS (HMSCS) TO THE OSTEOGENIC MECHANORESPONSE IN OBESE PATIENTS

Abstract

The induction of differentiation is a highly programmed lineage-specific process and several studies have provided great insight into the microenvironment affecting differentiation of multipotential hMSCs. In this regard, the importance of physical factors has been recognized for many years, but only little is known about its effects on undifferentiated hMSCs. The study aimed to determine the early osteogenic differentiation response to physiologically-based mechanical tensile strain with possible contributions to donor-specific physiological conditions.

MSCs of ten donors were expanded under standard culture conditions, and the individual response to cyclic tensile strain (CTS) was determined in a two-armed study design (strained versus unstrained (CTR)). CTS was applied with a maximum of 3,000 μstrain. Genotypic characteristics (RUNX2, ALPL, SPARC, SPP1; COL1A1, MKI67, etc) as well as phenotypic effects (cell numbers, cell viability and ALP activity) were compared between CTR and CTS, and possible relations to donor-specific physiological characteristics including anthropomorphometric and biochemical variables were determined.

We found a significant up-regulation of the osteogenic marker genes due to CTS, which was accompanied by an increase in cell-based ALP activity (plus 39.6 ± 9.8% SEM, P< 0.05). Cell density as well as XTT were significantly lower following CTS (minus 20.0 ± 4.7% and minus 17.8 ± 5.6%, respectively, P< 0.05). As a consequence, the ALP activity w/o normalization ranged widely from minus 30.8% to plus 60.1% between individual donors and was a function of donor’s BMI (r=−0.91, P< 0.0001), weight (r=−0.73, P=0.016), and age (r=−0.65, P=0.041).

The findings demonstrate that

1. the application of CTS provides an inherent osteogenic differentiation stimulus for undifferentiated hMSCs in vitro, and

2. the functional response of hMSCs to CTS was found to be highly related to donor’s BMI/fat mass, thus suggesting an upstream imprinting process of the hMSCs within bone marrow