Abstract: Cell-matrix interactions or disruption affects the cell cycle regulation in various ways and thus the extracellular Matrix (ECM) can control cell differentiation. In this study, Clara cells obtained form both wildtype (wt) and p21 knockout (p21 ko) mice were isolated and cultured on different ECM combinations. A lower expression of cytokeratins 8, 18 and 19 in unattached Clara cells from p21 knockout (ko) mice compared to wildtype (wt) mice was observed. The expressions of cytokeratin 8 and 19 were significantly higher in primary Clara cells cultures when laminin formed part of the ECM composition. The cell-matrix disruption also played an important part on Clara cells differentiation process.