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Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration.

ABSTRACT: The human endometrium undergoes sequential phases of shedding of the upper functionalis zone during menstruation, followed by regeneration of the functionalis zone from the remaining basalis zone cells, and secretory differentiation under the influence of the ovarian steroid hormones estradiol (E2) and progesterone (P4). This massive tissue regeneration after menstruation is believed to arise from endometrial stromal and epithelial stem cells residing in the basal layer of the endometrium. Although many endometrial pathologies are thought to be associated with defects in these stem cells, studies on their identification and regulation are limited, primarily due to lack of easily accessible animal models, as these processes are unique to primates. Here we describe a robust new method to study endometrial regeneration and differentiation processes using human endometrial tissue slice cultures incorporating an air-liquid interface into a 3D matrix scaffold of type I collagen gel, allowing sustained tissue viability over three weeks. The 3D collagen gel-embedded endometrial tissue slices in a double-dish culture system responded to ovarian steroid hormones, mimicking the endometrial changes that occur in vivo during the menstrual cycle. These changes included the E2-induced upregulation of Ki-67, estrogen receptor (ER), and progesterone receptor (PR) in all endometrial compartments and were markedly suppressed by both P4 and E2 plus P4 treatments. There were also distinct changes in endometrial morphology after E2 and P4 treatments, including subnuclear vacuolation and luminal secretions in glands as well as decidualization of stromal cells, typical characteristics of a progestational endometrium in vivo. This long-term slice culture method provides a unique in vivo-like microenvironment for the study of human endometrial functions and remodeling during early pregnancy and experiments on stem cell populations involved in endometrial regeneration and remodeling. Furthermore, this model has the potential to enable studies on several endometrial diseases, including endometrial cancers and pregnancy complications associated with defects in endometrial remodeling.

SUBMITTER: Muruganandan S

PROVIDER: S-EPMC7022976 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration.

Muruganandan Shanmugam S Fan Xiujun X Dhal Sabita S Nayak Nihar R NR

Biomolecules 20200114 1

The human endometrium undergoes sequential phases of shedding of the upper functionalis zone during menstruation, followed by regeneration of the functionalis zone from the remaining basalis zone cells, and secretory differentiation under the influence of the ovarian steroid hormones estradiol (E2) and progesterone (P4). This massive tissue regeneration after menstruation is believed to arise from endometrial stromal and epithelial stem cells residing in the basal layer of the endometrium. Altho ...[more]

PMID: 31947662

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Project description:Over the past twenty years, evidence has accumulated that biochemically and spatially defined networks of extracellular matrix, cellular components, and interactions dictate cellular differentiation, proliferation, and function in a variety of tissue and diseases. Modeling in vivo systems in vitro has been undeniably necessary, but when simplified 2D conditions rather than 3D in vitro models are used, the reliability and usefulness of the data derived from these models decreases. Thus, there is a pressing need to develop and validate reliable in vitro models to reproduce specific tissue-like structures and mimic functions and responses of cells in a more realistic manner for both drug screening/disease modeling and tissue regeneration applications. In adipose biology and cancer research, these models serve as physiologically relevant 3D platforms to bridge the divide between 2D cultures and in vivo models, bringing about more reliable and translationally useful data to accelerate benchtop to bedside research. Currently, no model has been developed for bone marrow adipose tissue (BMAT), a novel adipose depot that has previously been overlooked as "filler tissue" but has more recently been recognized as endocrine-signaling and systemically relevant. Herein we describe the development of the first 3D, BMAT model derived from either human or mouse bone marrow (BM) mesenchymal stromal cells (MSCs). We found that BMAT models can be stably cultured for at least 3?months in vitro, and that myeloma cells (5TGM1, OPM2 and MM1S cells) can be cultured on these for at least 2?weeks. Upon tumor cell co-culture, delipidation occurred in BMAT adipocytes, suggesting a bidirectional relationship between these two important cell types in the malignant BM niche. Overall, our studies suggest that 3D BMAT represents a "healthier," more realistic tissue model that may be useful for elucidating the effects of MAT on tumor cells, and tumor cells on MAT, to identify novel therapeutic targets. In addition, proteomic characterization as well as microarray data (expression of >22,000 genes) coupled with KEGG pathway analysis and gene set expression analysis (GSEA) supported our development of less-inflammatory 3D BMAT compared to 2D culture. In sum, we developed the first 3D, tissue-engineered bone marrow adipose tissue model, which is a versatile, novel model that can be used to study numerous diseases and biological processes involved with the bone marrow.

Dataset Information

Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration.

Publications

Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration.

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