Concise Review: Salivary Gland Regeneration: Therapeutic Approaches from Stem Cells to Tissue Organoids

The human salivary gland (SG) has an elegant architecture of epithelial acini, connecting ductal branching structures, vascular and neuronal networks that together function to produce and secrete saliva. This review focuses on the translation of cell‐ and tissue‐based research toward therapies for patients suffering from SG hypofunction and related dry mouth syndrome (xerostomia), as a consequence of radiation therapy or systemic disease. We will broadly review the recent literature and discuss the clinical prospects of stem/progenitor cell and tissue‐based therapies for SG repair and/or regeneration. Thus far, several strategies have been proposed for the purpose of restoring SG function: (1) transplanting autologous SG‐derived epithelial stem/progenitor cells; (2) exploiting non‐epithelial cells and/or their bioactive lysates; and (3) tissue engineering approaches using 3D (three‐dimensional) biomaterials loaded with SG cells and/or bioactive cues to mimic in vivo SGs. We predict that further scientific improvement in each of these areas will translate to effective therapies toward the repair of damaged glands and the development of miniature SG organoids for the fundamental restoration of saliva secretion. Stem Cells 2017;35:97–105Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135510/1/stem2455.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135510/2/stem2455_am.pd

Rescue of Salivary Gland Function after Stem Cell Transplantation in Irradiated Glands

Head and neck cancer is the fifth most common malignancy and accounts for 3% of all new cancer cases each year. Despite relatively high survival rates, the quality of life of these patients is severely compromised because of radiation-induced impairment of salivary gland function and consequential xerostomia (dry mouth syndrome). In this study, a clinically applicable method for the restoration of radiation-impaired salivary gland function using salivary gland stem cell transplantation was developed. Salivary gland cells were isolated from murine submandibular glands and cultured in vitro as salispheres, which contained cells expressing the stem cell markers Sca-1, c-Kit and Musashi-1. In vitro, the cells differentiated into salivary gland duct cells and mucin and amylase producing acinar cells. Stem cell enrichment was performed by flow cytrometric selection using c-Kit as a marker. In vitro, the cells differentiated into amylase producing acinar cells. In vivo, intra-glandular transplantation of a small number of c-Kit+ cells resulted in long-term restoration of salivary gland morphology and function. Moreover, donor-derived stem cells could be isolated from primary recipients, cultured as secondary spheres and after re-transplantation ameliorate radiation damage. Our approach is the first proof for the potential use of stem cell transplantation to functionally rescue salivary gland deficiency

CERE-120 Prevents Irradiation-Induced Hypofunction and Restores Immune Homeostasis in Porcine Salivary Glands

Salivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis

Elaboration et caracterisation de siliciures utilises comme materiaux de grille ou d'interconnexion dans les circuits VLSI

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Regeneration of irradiated salivary glands by stem cell therapy

Yearly, worldwide more than 500.000 new head and neck cancer patients are treated with radiotherapy. Co-irradiation of salivary glands may lead to xerostomia (=dry mouth syndrome), resulting in permanent loss of saliva production. This loss of gland function after radiation is thought to be due to a loss of stem cells that are no longer able to replenish saliva-producing acinar cells. Therefore, stem cell therapy could be utilized to prevent radiation-induced damage to the salivary gland. Bone marrow-derived (stem) cells (BMCs), when mobilized to the blood circulation, are able to contribute to the regeneration of acinar cells and blood vessels of irradiated mice salivary glands, resulting in increasing saliva production. Since only low percentages of acinar cells were BM-derived, the engrafted BMCs seem to secrete micro-environmental factors which stimulate radiation-surviving salivary gland stem/progenitor cells. Optimal recovery of irradiated salivary glands could possibly be obtained by increasing functional salivary gland stem cell numbers. This was accomplished by in vivo administration of Keratinocyte Growth Factor, which resulted in the formation of almost normal levels of acinar cell numbers and saliva production. A more clinical application could be obtained by transplanting in vitro cultured, characterized and isolated salivary gland stem cells. Serial transplantation of stem cells, expressing c-Kit, in irradiated salivary glands resulted in both functional as morphological improvement of damaged glands. Further, c-Kit+ cells could also be isolated from human salivary glands, which open perspectives for potential clinical stem cell transplantations post-irradiation. The concept of stem cell therapy, i.e. increasing the number of stem cell numbers via growth factors or via stem cell transplantations, could lead to a novel approach to prevent radiation-induced damage to normal organs, which is not necessarily limited to salivary glands.

Stem Cell Therapy to Reduce Radiation-Induced Normal Tissue Damage

Normal tissue damage after radiotherapy is still a major problem in cancer treatment. Stem cell therapy may provide a means to reduce radiation-induced side effects and improve the quality of life of patients. This review discusses the current status in stem cell research with respect to their potential to reduce radiation toxicity. A number of different types of stem cells are being investigated for their potential to treat a variety of disorders. Their current status, localization, characterization, isolation, and potential in stem cell-based therapies are addressed. Although clinical adult stem cell research is still at an early stage, preclinical experiments show the potential these therapies may have. Based on the major advances made in this field, stem cell-based therapy has great potential to allow prevention or treatment of normal tissue damage after radiotherapy. Semin Radiat Oncol 19:112-121 (C) 2009 Elsevier Inc. All rights reserved

Submandibular parasympathetic gangliogenesis requires sprouty-dependent Wnt signals from epithelial progenitors.

Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found that deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation, and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons, and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus, K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance