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Review
. 2003 Jun 15;116(Pt 12):2377-88.
doi: 10.1242/jcs.00503.

Modeling tissue-specific signaling and organ function in three dimensions

Karen L Schmeichel  1 , Mina J Bissell
Affiliations
Review

Modeling tissue-specific signaling and organ function in three dimensions

Karen L Schmeichel et al. J Cell Sci. .

Abstract

In order to translate the findings from basic cellular research into clinical applications, cell-based models need to recapitulate both the 3D organization and multicellular complexity of an organ but at the same time accommodate systematic experimental intervention. Here we describe a hierarchy of tractable 3D models that range in complexity from organotypic 3D cultures (both monotypic and multicellular) to animal-based recombinations in vivo. Implementation of these physiologically relevant models, illustrated here in the context of human epithelial tissues, has enabled the study of intrinsic cell regulation pathways and also has provided compelling evidence for the role of the stromal compartment in directing epithelial cell function and dysfunction. Furthermore the experimental accessibility afforded by these tissue-specific 3D models has implications for the design and development of cancer therapies.

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Figures

Fig. 1
Fig. 1
Hierarchical modeling of human breast function. Similarities between the organization of human and mouse mammary glands have enabled observations in one tissue to be transferred to the other. This dynamic exchange of information has led to the gradual development of mammary gland models that now represent a continuum of organotypic systems ranging in complexity from monotypic 3D cultures to multicellular co-cultures to in vivo xenograft models. Each of the 3D models depicted here represents a physiologically relevant assay in its own right. However, when engineered with common cellular components and used in series, these models become invaluable tools for the identification and verification of disease-related molecules as well as for the design and translation of effective drug therapies. Future in vivo models that are more faithful to the human mammary microenvironment may be achieved in a ‘humanized’ mouse model in which mammary glands are entirely repopulated by breast cell types of human origin. Ep, epithelial cell; Myoep, myoepithelial cell. Adapted from previous publications (Ronnov-Jessen et al., 1996; Schmeichel et al., 1998).
Fig. 2
Fig. 2
Signaling mechanisms studied in monotypic 3D cultures of human mammary epithelial cell lines. The phenotypes of human mammary epithelial cells can be readily distinguished in the context of 3D lrBM assays. After 10 days in culture, non-malignant cells form growth-arrested, polarized acini with central lumens, whereas malignant cells form apolar colonies of continually growing cells that vary in size and shape depending on the degree of tumorigenicity. A number of studies, some of which are depicted here, have utilized this assay to explore the molecular regulation of normal breast (e.g., lumen formation) as well as aberrant signaling during tumor progression and/or reversion. Individual studies are referenced in the text.
Fig. 3
Fig. 3
Using genetically engineered fibroblasts to elucidate stromal-epithelial interactions in organotypic skin co-cultures. Primary human keratinocytes maintain their stratified and differentiated morphology in 3D organotypic co-cultures regardless of whether dermal fibroblasts included are of human (HDF, A) or mouse (MEF, mouse embryonic fibroblasts, B) origin. Substitution of wild-type mouse fibroblasts with genetically engineered fibroblasts from transgenic animals allows for a detailed analysis of the molecular underpinnings of epithelial stromal interactions. Here, c-jun−/− (C) and junB−/− (D) fibroblasts are shown to have hypo- or hyperproliferative effects, respectively, on the morphology of human skin. This study demonstrates the utility of 3D co-culture methodologies in dissecting the molecular determinants of paracrine signaling networks. This figure is summarized from a previously published figure (Szabowski et al., 2000).
Fig. 4
Fig. 4
Modeling mammary acinar structure in 3D organotypic co-cultures. Purified primary human luminal epithelial cells were embedded and cultured in lrBM (A) or collagen I gels (B,C) in the absence (A,B) or presence (C) of purified myoepithelial cells (MEP). Cultures were double stained for the lumenal marker, sialomucin (red) and the basolateral marker, epithelial-specific antigen (ESA; green). Luminal epithelial cells form polarized organotypic spheres in lrBM but adopt inverse polarity in collagen I gels. Addition of purified myoepithelial cells to luminal epithelial cells in collagen I corrects acinar polarity (C) and results in formation of a bilayered organotypic structure. Reproduced with permission from Gudjonsson et al. (Gudjonsson et al., 2002a).
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