Laminin-1 Peptides Conjugated to Fibrin Hydrogels Promote Salivary Gland Regeneration in Irradiated Mouse Submandibular Glands.

Kihoon Nam,Pedro Lei,Harim T Dos Santos,Olga J Baker,Frank Maslow,Stelios T Andreadis,Bryan G Trump

doi:10.3389/fbioe.2021.729180

Abstract

Previous studies demonstrated that salivary gland morphogenesis and differentiation are enhanced by modification of fibrin hydrogels chemically conjugated to Laminin-1 peptides. Specifically, Laminin-1 peptides (A99: CGGALRGDN-amide and YIGSR: CGGADPGYIGSRGAA-amide) chemically conjugated to fibrin promoted formation of newly organized salivary epithelium both in vitro (e.g., using organoids) and in vivo (e.g., in a wounded mouse model). While these studies were successful, the model’s usefulness for inducing regenerative patterns after radiation therapy remains unknown. Therefore, the goal of the current study was to determine whether transdermal injection with the Laminin-1 peptides A99 and YIGSR chemically conjugated to fibrin hydrogels promotes tissue regeneration in irradiated salivary glands. Results indicate that A99 and YIGSR chemically conjugated to fibrin hydrogels promote formation of functional salivary tissue when transdermally injected to irradiated salivary glands. In contrast, when left untreated, irradiated salivary glands display a loss in structure and functionality. Together, these studies indicate that fibrin hydrogel-based implantable scaffolds containing Laminin-1 peptides promote secretory function of irradiated salivary glands.

Highlights

According to the American Cancer Society, each year more than 80,000 people develop head and neck cancer in the United States (Siegel et al, 2021)
These technologies offer the potential for more advanced solutions to hyposalivation due to head and neck radiation therapy but have yet to truly deliver. In response to these needs and challenges, we developed Fibrin Hydrogels (FH) with conjugated Laminin-1 peptides (L1p) A99 and YIGSR that were used successfully to repair salivary gland tissue in a wounded submandibular gland (SMG) mouse model (Nam et al, 2017a; Nam et al, 2017b; Nam et al, 2019b). To apply these results to a more translational setting, the goal of the current study is to determine whether transdermal injection with the L1p A99 and YIGSR chemically conjugated to FH can promote secretory function in irradiated salivary glands
To investigate whether L1p-FH could restore irradiated SMG structure and function, C57BL/6J mice were subjected to a single radiation treatment as described in Materials and Methods (Figure 1A)

Summary

Introduction

According to the American Cancer Society, each year more than 80,000 people develop head and neck cancer in the United States (Siegel et al, 2021). A first-line treatment for head and neck cancer is radiation therapy (Sroussi et al, 2017), but ionizing radiation typically leads to chronic oral complications such as xerostomia (i.e., hyposalivation) (Chambers et al, 2004; Grundmann et al, 2010; Jensen et al, 2010; Pinna et al, 2015; Sroussi et al, 2017; Jensen et al, 2019; Haderlein et al, 2020; Jasmer et al, 2020). Several experimental therapies including the use of stem cells (Nanduri et al, 2011; Nanduri et al, 2013; Pringle et al, 2013; Mitroulia et al, 2019; Su et al, 2020), embryonic organ culture (Ogawa et al, 2013; Ogawa and Tsuji, 2015; Ikeda et al, 2019), organ bioprinting (Ferreira et al, 2016; Adine et al, 2018), cell sheets (Nam et al, 2019a; dos Santos et al, 2020), gene therapy (Zheng et al, 2011; Baum et al, 2012; Arany et al, 2013) and bioengineered scaffolds (Peters et al, 2014; Foraida et al, 2017; Patil and Nanduri, 2017; Nam et al, 2019b) have offered the promise of more advanced solutions as detailed below

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