Mesenchymal Stem Cell Deformability and Implications for Microvascular Sequestration

Mesenchymal stem cells (MSCs) have received considerable attention in regenerative medicine, particularly in light of prospects for targeted delivery by intra-arterial injection. However, little is known about the mechanics of MSC sequestration in the microvasculature and the yield pressure (P (Y)), above which MSCs will pass through microvessels of a given diameter. The objectives of the current study were to delineate the dependency of P-Y on cell size and the heterogeneity of cell mechanical properties and diameters (D (CELL)) of cultured MSCs. To this end the transient filtration test was employed to elucidate the mean filtration pressure (< P-Y >) for an ensemble of pores of a given size (D (PORE)) similar to in vivo microvessels. Cultured MSCs had a log-normal distribution of cell diameters (D (CELL)) with a mean of 15.8 +/- 0.73 SD mu m. MSC clearance from track-etched polycarbonate filters was studied for pore diameters of 7.3-15.4 mu m. The pressure required to clear cells from filters with 30-85 x 10(3) pores rose exponentially with the ratio lambda = D (CELL) /D (PORE) for 1.1 <= lambda <= 2.2. The clearance of cells from each filter was characterized by a log-normal distribution in P (Y), with a mean filtration pressure of 0.02 <= < P-Y > <= 6.7 cmH(2)O. For lambda <= 1.56, the yield pressure (P-Y) was well represented by the cortical shell model of a cell with a viscous interior encapsulated by a shell under cortical tension tau(0) = 0.99 +/- 0.42 SD dyn/cm. For lambda > 1.56, the < P-Y > characteristic of the cell population rose exponentially with lambda. Analysis of the mean filtration pressure (< P-Y >) of each sample suggested that the larger diameter cells that skewed the distribution of D (CELL) contributed to about 20% of the mean filtration pressure. Further, if all cells had the same deformability (i.e., P (Y) as a function of lambda) as the average cell population, then < P-Y > would have risen an order of magnitude above the average from fivefold at lambda = 1.56 to 200-fold at lambda = 2.1. Comparison of < P-Y > to published microvascular pressures suggested that < P-Y > may exceed microvessel pressure drops for lambda exceeding 2.1, and rise 14-fold above capillary pressure drop at lambda = 3 leading to 100% sequestration. However, due to the large variance of in vivo microvascular pressures entrapment of MSCs may be mitigated. Thus it is suggested that selecting fractions of the MSC population according to cell deformability may permit optimization of entrapment at sites targeted for tissue regeneration.