TGF-BETA-1 INFLUENCES THE RELATIVE DEVELOPMENT OF THE EXOCRINE AND ENDOCRINE PANCREAS IN-VITRO

Pancreatic rudiments from E12.5 mouse embryos undergo extensive develo pment and differentiation when cultured in three-dimensional gels of e xtracellular matrix proteins for up to 12 days, Whereas collagen gels promote the formation of numerous exocrine acini and relatively small clusters of endocrine cells, in basement membrane (EHS) matrices the d evelopment of endocrine cells is dramatically favoured over that of ac inar tissue, Buds embedded in a collagen gel contiguous to an EHS gel also fail to develop acini, suggesting the involvement of diffusible f actor(s). Addition of cytokines to cultures of pancreatic buds in coll agen gels modifies the relative proportions of the epithelial componen ts of the gland, In the presence of EGF the proportion of the tissue o ccupied by ducts overrides that of acinar structures, whereas the endo crine portion of the tissue is not significantly modified. TGF-beta 1 partially mimicks the effect of EHS matrix in inhibiting the developme nt of acinar tissue without decreasing the amount of ducts and mesench yme; TGF-beta 1 also promotes the development of endocrine cells, in p articular of insulin-containing beta cells and of cells expressing gen es of the PP-fold family, These results show that cytokines can modula te the development of the pancreas and suggest a role for TGF-beta 1 i n regulating the balance between the acinar and endocrine portions of the gland in vivo, More generally, they are compatible with the notion that, during organogenesis, cytokines act as paracrine factors respon sible for the development and maintenance of appropriate proportions o f different tissue constituents.