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Differentiation, Dedifferentiation, and Transdifferentiation of BALB/C 3T3 T Mesenchymal Stem Cells: Potential Significance in Metaplasia and Neoplasia1

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Differentiation, Dedifferentiation, and Transdifferentiation of BALB/C 3T3 T Mesenchymal Stem Cells: Potential Significance in Metaplasia and Neoplasia1 [CANCER RESEARCH 46, 5312-5319, October 1986] Differentiation, Dedifferentiation, and Transdifferentiation of BALB/c 3T3 T Mesenchymal Stem Cells: Potential Significance in Metaplasia and Neoplasia1 Rodney L. Sparks, Elizabeth I. Seibel-Ross, Marjorie L. Wier, and Robert E. Scott2 Section of Experimental Pathology, Departments of Pathology and Biochemistry and Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota 55905 ABSTRACT process by which normal cells develop variations in cell size, shape, proliferation, and differentiation. The expression of defects in the control of cellular differentiation is The underlying mechanisms by which the expression of de thought to be of etiological significance in the early stages of carcinogen- fects in the control of differentiation could be associated with esis. This possibility is supported by a variety of experimental studies the development of metaplastic, dysplastic, preneoplastic, and including those that have established that metaplastic changes in cells neoplastic states are not clear. The hypothesis we favor suggests can represent preneoplastic lesions in vivo. To evaluate this question in that in normal stem cells the integrated control of cellular greater detail, we have used 3T3 T mesenchymal stem cells as a model system. These cells express certain characteristics of preneoplastic cells differentiation and proliferation is stringently regulated, even though they can regulate their proliferation and even though they whereas in metaplastic, dysplastic, preneoplastic, and neoplas can undergononterminaland terminal differentiation into adipocytes. For tic cells, these stringent regulatory mechanisms are partially or example, they are immortal and aneuploid, and they show a proclivity to completely abrogated. As a result such cells would be expected undergo spontaneous or induced neoplastic transformation compared to to show aberrant differentiation and/or proliferation (4, 7, 9- normal human cells. The question we sought to answer in the current 22). In this regard, the term "stringent integrated control" experiments concerns whether predifferentiation growth arrest and/or describes the ability of stem cells or progenitor cells to make nonterminal differentiation in such preneoplastic cells is completely specific "decisions" that result in the expression of a specific reversible or whether these processes induce the expression of the new set of genes that stably programs the cells' subsequent prolif stable program that limits the cells' proliferativi' potential and reduces the cells' subsequent differentiation potential in a manner comparable to eration and differentiation potentialities. that which is thought to occur in normal stem cells. The results show A major focus of our experimental studies on carcinogenesis that arrest at both the predifferentiation state and at the nonterminal has therefore been directed at attempts to establish the biolog differentiation state is a completely reversible phenomenon that does not ical and molecular mechanisms that control cellular differentia limit the cells1 subsequent growth or differentiation potential. In fact, the tion in normal, preneoplastic, and cancerous cells. One diffi results show that, when nonterminally differentiated 3T3 T adipocytes culty with such an approach is to identify a model cell system are induced to dedifferentiate, they can subsequently redifferentiate into with which to study mechanisms for the regulation of cellular macrophages. We therefore suggest that preneoplasia as expressed in differentiation and its integral relationship to the control of 3T3 T mesenchymal stem cells is associated with the expression of cellular proliferation. In this regard, many cell systems have defects in the ability to integrally control cellular differentiation and proliferation. As a result, the data suggest that such cells express an been used in the past, but none has proven to be ideal. The increased proclivity to undergo metaplastic change and complete neo reason for this is that the control of growth and differentiation plastic transformation. in many model systems is regulated by highly variable or poorly defined regulatory mechanisms. For example, in some differ entiation systems specific physiological polypeptides are re INTRODUCTION quired to induce differentiation (7, 10, 20, 23-30), whereas in others they are not (8, 11, 12, 21, 22, 31-43). In some cells Carcinogenesis is a multistep process that has been reported DNA synthesis is required before expression of the differen to develop in association with the expression of defects in the tiated phenotype (11, 22, 27, 33), whereas in other cells it is control of both cellular proliferation and differentiation (1-8). not (26, 29, 31, 38-40, 42). Furthermore, in some cell types Recent studies furthermore suggest that the expression of de part of the differentiation program is reversible (23, 25, 26, 29, fects in the control of differentiation may occur in the early 32, 33, 35, 40), whereas in others it appears to be irreversible stages of carcinogenesis. For example, it has recently been (8,31,36,42,43). shown that UV irradiation, at dosages that initiate carcinogen By contrast, normal stem cells and/or progenitor cells appear esis, induces stable and heritable defects in stem cell differen to possess stringent regulatory mechanisms that integrate the tiation (7), and it has been demonstrated that an initiating control of cellular proliferation and differentiation. This con dosage of carcinogen can induce specific defects in the ability clusion is primarily based on in vitro studies using cells such as of mouse epidermal cells to terminally differentiate (8). The normal diploid human epidermal cells and hemopoietic stem fact that many metaplastic and dysplastic disease states that cells (1, 43-46). The expression of such stringent mechanisms are associated with aberrant differentiation represent preneo to integrally regulate cellular differentiation and proliferation plastic lesions also supports this conclusion. In this regard, correlates very well with the fact that normal cells, especially metaplasia is the process in which a normal stem cell changes those derived from humans and hamsters, show an extremely its pathway of differentiation so that one adult cell type is low frequency of spontaneous or carcinogen-induced neoplastic replaced by a different adult cell type, and dysplasia is the transformation (4, 5, 19, 45, 46). Received 11/19/85; revised 7/7/86; accepted 7/9/86. The goal of our current studies was to determine whether or The costs of publication of this article were defrayed in part by the payment not preneoplastic BALB/c 3T3 T mesenchymal stem cells can of page charges. This article must therefore be hereby marked advertisement in be demonstrated to possess defects in their regulatory mecha accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1Supported by NIH Grant CA 28240andby the Mayo Foundation to R. E. S. nisms that integrally control cellular differentiation and prolif R. L. S. was partially funded by National Cancer Institute Training Grant CA eration. That is, in these studies we specifically evaluated 09441. 2To whom requests for reprints should be addressed, at 51 IB Guggenheim whether the induction of differentiation activates a program Building, Mayo Clinic, Rochester, MN 55905. that limits cell proliferation and also limits the differentiation 5312 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1986 American Association for Cancer Research. DIFFERENTIATION DEFECTS, METAPLASIA AND NEOPLASIA ensure that cultures were free of Mycoplasma contamination, the cells were periodically assayed by the method of Chen (51). New stock cultures were thawed from liquid nitrogen every 2 to 3 mo. Preparation of Plasma and Plasma Fractions That Induce Adipocyte Differentiation. The preparation of human plasma and plasma fractions that were used to induce differentiation in these cells has been described in detail elsewhere (26, 29, 30). Briefly, citrate-anticoagulated platelet- poor human plasma was derived from venous blood of normal donors. TD This fluid was used in its native state following further processing. Fractionation of human plasma was carried out according to a modifi cation of the technique described by Mann (52). More specifically, liai Õ.was added to citrate-anticoagulated human plasma to a final concentration of 0.1 M, and this solution was then adjusted to pH 8.6. It was stirred for 30 min and then sedimented by centrifugation at 3600 x g for 25 min. The supernatant was removed, and the barium citrate sediment, designated the cake, was then partially solubilized by the addition of 0.9% NaCl solution: 0.02 M sodium citrate to bring the Fig. 1. Illustration of the stages of adipocyte differentiation of 3T3 T mesen- volume to one-third of the original volume of plasma that was present chymal stem cells that are regulated during the G, phase of the cell cycle. Each when the BaCI2 was added. This suspension was stirred for 45 min and step is a prerequisite for the next step to occur, and once a cell has achieved the then subjected to centrifugation at 3600 x g for 25 min. The supernatant properties of a specific state, it is competent to respond to the signal(s) that induces progression to the next state. First, cells growth arrest at a specific state was saved and was designated CEPH (26, 29, 30). This plasma fraction in the G, phase of the cell cycle, designated GD(Arrow 1). Such cells
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