Mechanical properties of cells reflect their unique physiological status. Methods for direct measurement of these properties and their applications are required for cell therapy and diagnostics. Young's modulus of the cell and nuclear surfaces of human mesenchymal stem cells (hMSCs) were measured using atomic force microscopy with a cone-shaped probe. Young's moduli of the cell surface and bare exposed nuclear surface of hMSCs were 54.3 +/- 37.37 kPa and 1.11 +/- 0.58 kPa, respectively. The height of the bare nucleus was three times greater than that of an intact cell. Although the normal cell surface showed membrane penetrability with the cone-shaped probe, the bare nucleus was impenetrable. By de-polymerizing the actin filaments, Young's modulus of the hMSCs was reduced to 3.05 +/- 2.77 kPa, and the height of the cell increased such that it was similar to that of the bare nucleus. Disruption of the actin cytoskeleton makes the cell surface impenetrable. However, the nuclear structure maintains the penetrability of cell membrane in an actin de-polymerized cell. Rigidity and penetrability of the cell membrane are maintained by the actin cytoskeleton, and the nuclear structure supports the cell surface under conditions of actin de-polymerization. (C) 2009 Elsevier B.V. All rights reserved.