Abstract
Radiotherapy for head and neck cancer often has undesirable effects on salivary glands that lead to xerostomia or severe dry mouth, which can increase oral infections. Our goal is to engineer functional, three‐dimensional (3D) salivary gland neotissue for autologous implantation to provide permanent relief. An immediate need exists to obtain autologous adult progenitor cells as the use of embryonic and induced pluripotent stem cells potentially pose serious risks such as teratogenicity and immunogenic rejection. Here, we report an expandable population of primary salivary human stem/progenitor cells (hS/PCs) that can be reproducibly and scalably isolated and propagated from tissue biopsies. These cells have increased expression of progenitor markers (K5, K14, MYC, ETV4, ETV5) compared with differentiation markers of the parotid gland (acinar: MIST1/BHLHA15 and AMY1A; ductal: K19 and TFCP2L1). Isolated hS/PCs grown in suspension formed primary and secondary spheres and could be maintained in long‐term 3D hydrogel culture. When grown in a customized 3D modular hyaluronate‐based hydrogel system modified with bioactive basement membrane‐derived peptides, levels of progenitor markers, indices of proliferation, and viability of hS/PCs were enhanced. When appropriate microenvironmental cues were provided in a controlled manner in 3D, such as stimulation with β‐adrenergic and cholinergic agonists, hS/PCs differentiated into an acinar‐like lineage, needed for saliva production. We conclude that the stem/progenitor potential of adult hS/PCs isolated without antigenic sorting or clonal expansion in suspension, combined with their ability to differentiate into specialized salivary cell lineages in a human‐compatible culture system, makes them ideal for use in 3D bioengineered salivary gland applications. Stem Cells Translational Medicine 2017;6:110–120
Highlights
Head and neck cancer is the fifth most common cancer in United States, accounting for 3%–5% of all malignancies
We conclude that the stem/progenitor potential of adult human stem/ progenitor cells (hS/PCs) isolated without antigenic sorting or clonal expansion in suspension, combined with their ability to differentiate into specialized salivary cell lineages in a human-compatible culture system, makes them ideal for use in 3D bioengineered salivary gland applications
To evaluate the mRNA levels of stem/progenitor markers in primary cells freshly isolated from Human parotid gland (hPG) tissue, Quantitative polymerase chain reactions (qPCRs) was performed for previously reported stem/progenitor markers in salivary gland tissue (Fig. 1A)
Summary
Head and neck cancer is the fifth most common cancer in United States, accounting for 3%–5% of all malignancies. Differentiation of Salivary Stem/Progenitor Cells bioengineer autologous salivary gland neotissue to restore salivary function for patients suffering from radiation-induced xerostomia. A major milestone in organ engineering involves the identification and isolation of stem/progenitor cells that can be differentiated into desired functional cell types by providing them with appropriate extracellular stimuli. The potential use of induced pluripotent stem cells (iPSCs) and bone marrow stem cells (BMSCs) has been evaluated for salivary gland restoration [3,4,5]. The isolation of autologous salivary gland adult stem/ progenitors reintroduced to the xerostomia patient can circumvent these challenges both by their lack of immunogenicity and by their potential to be differentiated into the desired cell type by providing the appropriate microenvironment
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