Human Bone Marrow Cell Extracts Mitigate Radiation Injury to Salivary Gland

Abstract

Mitigation of irradiation injury to salivary glands was previously reported using a cell-free extract from mouse bone marrow. However, to bring this potential therapy a step closer to clinical application, a human bone marrow cell extract (BMCE) needs to be tested. Here, we report that irradiation-induced injury of salivary glands in immunocompetent mice treated with human BMCE secreted 50% more saliva than saline-injected mice, and BMCE did not cause additional acute inflammatory reaction. In addition, to identify the cell fraction in BMCE with the most therapeutic activity, we sorted human bone marrow into 3 cell fractions (mononuclear, granulocyte, and red blood cells) and tested their respective cell extracts. We identified that the mononuclear cell extract (MCE) provided the best therapeutic efficacy. It increased salivary flow 50% to 73% for 16 wk, preserved salivary parenchymal and stromal cells, and doubled cell proliferation rates while producing less inflammatory response. In contrast, the cell extract of granulocytes was of shorter efficacy and induced an acute inflammatory response, while that from red blood cells was not therapeutically effective for salivary function. Several proangiogenic (MMP-8, MMP-9, VEGF, uPA) and antiangiogenic factors (TSP-1, PF4, TIMP-1, PAI-1) were identified in MCE. Added advantages of BMCE and MCE for potential clinical use were that cell extracts from both male and female donors were comparably bioactive and that cell extracts could be stored and transported much more conveniently than cells. These findings suggest human BMCE, specifically the MCE fraction, is a promising therapy against irradiation-induced salivary hypofunction.

Recent progress in regenerative therapy for damaged salivary glands: From bench to bedside

“…This approach exhibited a therapeutic effect comparable to MSCs in NOD mice (Abughanam et al, 2019). Another study showed that this strategy can be used to treat irradiation‐injured SGs, as cell extracts of adipose‐ and BM‐derived MSCs or salivary gland stem cell containing numerous angiogenesis‐related growth factors restored the function of radiogenic SGs (Fang et al, 2018; Su et al, 2020; Su, Liu, et al, 2022; Su, Pillai, et al, 2022). Additionally, our preliminary data demonstrated that cell extracts do not accelerate tumor growth.…”

Cell-Free Biologics: Focus on Mesenchymal Stem Cell Conditioned Media

“…Так, для отримання кріоекстракту клітин культивовані чи нативні клітини ресуспендують у 0,9 % фізіологічному розчині до концентрації 10 7 клітин/100 мкл та проводять 3 цикли заморожування (-80°C) та відтавання (37°C) для лізису клітин. Після центрифугування при 17000 g протягом 30 хв при 4°C супернатант (визначений як клітиннй екстракт) зберігають при -80°C до використання [9,10,11].…”

Immunomodulatory Macrophages Enable E-MNC Therapy for Radiation-Induced Salivary Gland Hypofunction

“…To date, various experimental approaches of cell-based therapy employing gland epithelial stem/progenitor cells and/or mesenchymal stem cells (MSCs) have been examined for restoring the function of IR-damaged SGs [10][11][12][13][14][15][16]. Among these approaches, MSC therapy for atrophic SGs using intraglandular or intravenous injection of cells has been shown to slow the atrophic process by paracrine effects via induction of polarization of activated macrophages towards an anti-inflammatory phenotype (M2-type) at injury sites [13][14][15][16][17][18]. These macrophages contribute to revascularization and the following tissue regeneration [19][20][21].…”