Spontaneous and radiation-induced differentiationof fibroblasts.

Clonal heterogeneity in fibroblast cultures from donors of all ages has been associated with differentiation of the fibroblast/fibrocyte system. Thus, a terminal differentiation lineage including a sequence of three potentially mitotic progenitor fibroblasts (MFI-->MFII-->MFIII) in the precursor compartment and three types of postmitotic fibrocytes (PMFIV-->PMFV-->PMFVI) in the functional compartment has been identified previously. In the present study, we show that replenishment of fibrocytes lost from the functional compartment is not expected to change the distribution of differentiation types in a steady state population, provided cell loss occurs at the end of a long sequence of cell divisions only. However, premature terminal differentiation of progenitor fibroblasts to postmitotic fibrocytes can be induced by ionising radiation and other cell stressors. Furthermore, even a low dose of 1Gy causes a change in the distribution of surviving MF progenitor cells towards later differentiation stages within the precursor compartment. The role of autocrine transforming growth factor-beta1 production by fibroblasts in mediating terminal differentiation was investigated. We propose that cell stress and DNA damaging agents may contribute to progression of the differentiation state with age and that individual variation may be related to differences in the rate of induced differentiation.