Specific complexes derived from extracellular matrix facilitate generation of structural and drug‐responsive human salivary gland microtissues through maintenance stem cell homeostasis

Abstract

Three‐dimensional cultured salivary glands (SGs) microtissues hold great potentials for clinical research. However, most SGs microtissues still lack convincing structure and function due to poor supplementation of factors to maintain stem cell homeostasis. Extracellular matrix (ECM) plays a crucial role in regulating stem cell behavior. Thus, it is necessary to model stem cell microenvironment in vitro by supplementing culture medium with proteins derived from ECM. We prepared specific complexes from human SG ECM (s‐Ecx) and analyzed the components of the s‐Ecx. Human SG epithelial and mesenchymal cells were used to generate microtissues, and the optimum seeding cell number and ratio of two cell types were determined. Then, the s‐Ecx was introduced to the culture medium to assess its effect on stem cell behavior. Multiple specific factors were presented in s‐Ecx. s‐Ecx promoted maintenance of the stem cell and formation of specific structures resembling that of salivary glands and containing mucins, which suggested stem cell differentiation potential. Moreover, treatment of the microtissues with s‐Ecx increased their sensitivity to neurotransmitters. On the basis of the analysis of components, we believed that the presented growth factors are able to interact with stem cell they encountered in vivo, which promote the capacity to maintain stem cell homeostasis. This work provided foundations to study molecular mechanism of stem cell homeostasis in SGs and develop novel therapies for dry mouth through new drug discovery and disease modeling.

Thermoresponsive fiber-based microwells capable of formation and retrieval of salivary gland stem cell spheroids for the regeneration of irradiation-damaged salivary glands

“…53,54 Furthermore, salivary gland ECM is known to incorporate and release these growth factors to maintain the SGSC homeostasis microenvironment. 55 Although the key factors involved in anti-apoptotic radioprotection and tissue remodeling after irradiation must be identified, we observed that SGSC spheroid cell-implanted mice experienced lower levels of radiation-induced tissue damage through enhanced radioprotective effects, compared with SGSC monolayer cellimplanted mice during observational study for 16 weeks post-irradiation.…”

Salivary Gland Tissue Engineering Approaches: State of the Art and Future Directions

“…For example, fibronectin induced branching and ductal elongation [ 85 ], which was enhanced with FGF7. Salivary gland ECM extract (s-Ecx) promoted a compact sphere structure and increased expression of keratins (K5, K7, K14, K19) and acinar markers such as Aqp5 and Muc-1 [ 86 ]. Chitosan has been shown to increase spheroid size and polarization [ 25 ], with the greatest effect from soluble chitosan.…”

Integration of organoids in peptide drug discovery: rise of the high-throughput screening

“…They can recapitulate the structural and functional features of their in vivo counterparts [17][18][19] . Compared to time-consuming animal models, organoids are easy to establish and manipulate [20][21][22][23][24][25][26][27][28][29] . Importantly, they can be used to study the mechanism of human diseases that are difficult to model in animals 25,30,31 .…”