Differentiation, dedifferentiation, and transdifferentiation of BALB/c 3T3 T mesenchymal stem cells: potential significance in metaplasia and neoplasia.

The expression of defects in the control of cellular differentiation is thought to be of etiological significance in the early stages of carcinogenesis. This possibility is supported by a variety of experimental studies including those that have established that metaplastic changes in cells can represent preneoplastic lesions in vivo. To evaluate this question in greater detail, we have used 3T3 T mesenchymal stem cells as a model system. These cells express certain characteristics of preneoplastic cells even though they can regulate their proliferation and even though they can undergo nonterminal and terminal differentiation into adipocytes. For example, they are immortal and aneuploid, and they show a proclivity to undergo spontaneous or induced neoplastic transformation compared to normal human cells. The question we sought to answer in the current experiments concerns whether predifferentiation growth arrest and/or nonterminal differentiation in such preneoplastic cells is completely reversible or whether these processes induce the expression of the new stable program that limits the cells' proliferative potential and reduces the cells' subsequent differentiation potential in a manner comparable to that which is thought to occur in normal stem cells. The results show that arrest at both the predifferentiation state and at the nonterminal differentiation state is a completely reversible phenomenon that does not limit the cells' subsequent growth or differentiation potential. In fact, the results show that, when nonterminally differentiated 3T3 T adipocytes are induced to dedifferentiate, they can subsequently redifferentiate into macrophages. We therefore suggest that preneoplasia as expressed in 3T3 T mesenchymal stem cells is associated with the expression of defects in the ability to integrally control cellular differentiation and proliferation. As a result, the data suggest that such cells express an increased proclivity to undergo metaplastic change and complete neoplastic transformation.