Resident CD34-positive cells contribute to peri-endothelial cells and vascular morphogenesis in salivary gland after irradiation

Takashi I,Yuichiro Ueda,Izumi Asahina,Yoshinori Sumita,Philipp Wörsdörfer,Süleyman Ergün

doi:10.1007/s00702-020-02256-1

Takashi I, Yuichiro Ueda + Show 4 more

Open Access

https://doi.org/10.1007/s00702-020-02256-1

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Abstract

Salivary gland (SG) hypofunction is a common post-radiotherapy complication. Besides the parenchymal damage after irradiation (IR), there are also effects on mesenchymal stem cells (MSCs) which were shown to contribute to regeneration and repair of damaged tissues by differentiating into stromal cell types or releasing vesicles and soluble factors supporting the healing processes. However, there are no adequate reports about their roles during SG damage and regeneration so far. Using an irradiated SG mouse model, we performed certain immunostainings on tissue sections of submandibular glands at different time points after IR. Immunostaining for CD31 revealed that already one day after IR, vascular impairment was induced at the level of capillaries. In addition, the expression of CD44—a marker of acinar cells—diminished gradually after IR and, by 20 weeks, almost disappeared. In contrast, the number of CD34-positive cells significantly increased 4 weeks after IR and some of the CD34-positive cells were found to reside within the adventitia of arteries and veins. Laser confocal microscopic analyses revealed an accumulation of CD34-positive cells within the area of damaged capillaries where they were in close contact to the CD31-positive endothelial cells. At 4 weeks after IR, a fraction of the CD34-positive cells underwent differentiation into α-SMA-positive cells, which suggests that they may contribute to regeneration of smooth muscle cells and/or pericytes covering the small vessels from the outside. In conclusion, SG-resident CD34-positive cells represent a population of progenitors that could contribute to new vessel formation and/or remodeling of the pre-existing vessels after IR and thus, might be an important player during SG tissue healing.

Highlights

The treatment for many patients with head and neck cancer is usually radiotherapy either alone or in combination with surgery and chemotherapy
This study demonstrates that Salivary gland (SG)-resident CD34-positive cells have the capability to contribute to morphogenesis of new vessels and stroma formation in SG after IR in mice
Asterisk represents statistical significance compared with no irradiated submandibular glands (*p < 0.05). e–g Double immunofluorescence staining for CD34 (Green) and CD31 (Red) in submandibular glands with no IR (e) and at 4-weeks (f), and 20-weeks (g) after IR

Summary

Introduction

The treatment for many patients with head and neck cancer is usually radiotherapy either alone or in combination with surgery and chemotherapy. Despite many advances in modern highprecision radiotherapy techniques such as 3-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiation therapy (IMRT), the treatment still results in irreversible SG damage (e.g. xerostomia, dysphagia, dental caries, oropharyngeal infections, and oral mucositis (Seiwert and Cohen 2005; St John et al 2006; Braam et al 2006) Among these side effects, radiation-induced xerostomia is the most common complication of radiotherapy for head and neck cancer, significantly lowering the quality of life in the long-term survivors (Malouf et al 2003; Trotti et al 2003; Dirix et al 2006). There are currently no satisfying therapies for patients with such SG hypofunction

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