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Development of human ectocervical tissue models with physiologic endocrine and paracrine signaling†.

ABSTRACT: There is a shortage of research models that adequately represent the unique mucosal environment of human ectocervix, limiting development of new therapies for treating infertility, infection, or cancer. We developed three microphysiologic human ectocervix models to study hormone action during homeostasis. First, we reconstructed ectocervix using decellularized extracellular matrix scaffolds, which supported cell integration and could be clinically useful. Secondly, we generated organotypic systems consisting of ectocervical explants co-cultured with murine ovaries or cycling exogenous hormones, which mimicked human menstrual cycles. Finally, we engineered ectocervix tissue consisting of tissue-specific stromal-equivalents and fully-differentiated epithelium that mimicked in vivo physiology, including squamous maturation, hormone response, and mucin production, and remained viable for 28 days in vitro. The localization of differentiation-dependent mucins in native and engineered tissue was identified for the first time, which will allow increased efficiency in mucin targeting for drug delivery. In summary, we developed and characterized three microphysiologic human ectocervical tissue models that will be useful for a variety of research applications, including preventative and therapeutic treatments, drug and toxicology studies, and fundamental research on hormone action in a historically understudied tissue that is critical for women's health.

SUBMITTER: McKinnon KE

PROVIDER: S-EPMC7608514 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Development of human ectocervical tissue models with physiologic endocrine and paracrine signaling†.

McKinnon Kelly E KE Sensharma Rhitwika R Williams Chloe C Ravix Jovanka J Getsios Spiro S Woodruff Teresa K TK

Biology of reproduction 20200801 3

There is a shortage of research models that adequately represent the unique mucosal environment of human ectocervix, limiting development of new therapies for treating infertility, infection, or cancer. We developed three microphysiologic human ectocervix models to study hormone action during homeostasis. First, we reconstructed ectocervix using decellularized extracellular matrix scaffolds, which supported cell integration and could be clinically useful. Secondly, we generated organotypic syste ...[more]

PMID: 32401296

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Project description:Cardiac excitation-contraction coupling (ECC) is the orchestrated process of initial myocyte electrical excitation, which leads to calcium entry, intracellular trafficking, and subsequent sarcomere shortening and myofibrillar contraction. Neurohumoral β-adrenergic signaling is a well-established mediator of ECC; other signaling mechanisms, such as paracrine signaling, have also demonstrated significant impact on ECC but are less well understood. For example, resident heart endothelial cells are well-known physiological paracrine modulators of cardiac myocyte ECC mainly via NO and endothelin-1. Moreover, recent studies have demonstrated other resident noncardiomyocyte heart cells (eg, physiological fibroblasts and pathological myofibroblasts), and even experimental cardiotherapeutic cells (eg, mesenchymal stem cells) are also capable of altering cardiomyocyte ECC through paracrine mechanisms. In this review, we first focus on the paracrine-mediated effects of resident and therapeutic noncardiomyocytes on cardiomyocyte hypertrophy, electrophysiology, and calcium handling, each of which can modulate ECC, and then discuss the current knowledge about key paracrine factors and their underlying mechanisms of action. Next, we provide a case example demonstrating the promise of tissue-engineering approaches to study paracrine effects on tissue-level contractility. More specifically, we present new functional and molecular data on the effects of human adult cardiac fibroblast conditioned media on human engineered cardiac tissue contractility and ion channel gene expression that generally agrees with previous murine studies but also suggests possible species-specific differences. By contrast, paracrine secretions by human dermal fibroblasts had no discernible effect on human engineered cardiac tissue contractile function and gene expression. Finally, we discuss systems biology approaches to help identify key stem cell paracrine mediators of ECC and their associated mechanistic pathways. Such integration of tissue-engineering and systems biology methods shows promise to reveal novel insights into paracrine mediators of ECC and their underlying mechanisms of action, ultimately leading to improved cell-based therapies for patients with heart disease.

Dataset Information

Development of human ectocervical tissue models with physiologic endocrine and paracrine signaling†.

Publications

Development of human ectocervical tissue models with physiologic endocrine and paracrine signaling†.

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