Bone progeria diminished the therapeutic effects of bone marrow mesenchymal stem cells on retinal degeneration

https://doi.org/10.1016/j.bbrc.2020.07.007Get rights and content

Highlights

  • 6 months old SAMP6 mice demonstrated retinal degeneration.

  • BMMSCs derived from SAMP6 mice failed to prevent retinal morphological degeneration and functional decline.

  • SAMR1-MSC transplantation counteracted retinal degeneration with increased NDRG2 expression.

Abstract

Senescence is closely related to the occurrence of retinal degeneration. Recent studies have shown that bone marrow mesenchymal stem cells (BMMSCs) have significant therapeutic effects on retinal degeneration, While BMMSCs suffer from functional decline in bone aging. Whether senescence affects BMMSCs therapy on retinal degeneration remains unknown. Here, we applied the previously established bone progeria animal model, the senescence-accelerated mice-prone 6 (SAMP6) strain, and surprisingly discovered that SAMP6 mice demonstrated retinal degeneration at 6 months old. Furthermore, BMMSCs derived from SAMP6 mice failed to prevent MNU-induced retinal degeneration in vivo. As expected, BMMSCs from SAMP6 mice exhibited impairment in the differentiation capacities, compared to those from the age-matched senescence-accelerated mice-resistant 1 (SAMR1) strain. Moreover, BMMSCs from SAMR1 mice counteracted MNU-induced retinal degeneration, with increased expression of the retina survival hallmark, N-myc downstream regulated gene 2 (NDRG2). Taken together, these findings reveal that bone progeria diminished the therapeutic effects of BMMSC on retinal degeneration.

Introduction

With the advancement of age, increasing elders are becoming susceptible to retinal degenerative diseases. These patients are presented as progressive deterioration of visual function and ultimate blindness, whereas confirmable treatments are still lacking [1]. Recent studies have reported that mesenchymal stem cell transplantation (MSCT) is beneficial for counteracting retinal degeneration. However, the regulatory factors of MSCT effects on retinal degeneration remain unknown.

Due to easily available and lower immunogenicity, bone marrow mesenchymal stem cells (BMMSCs) are widely used as feasible candidates in MSC transplantation (MSCT) [2]. Notably, BMMSCs used must comply with a set of criteria as quality control for therapy. Particularly, BMMSCs applied in MSCT should be derived from young donors, as senescence induces BMMSCs loss of stemness and may inhibit therapeutic effects [3]. Nevertheless, whether aging of BMMSCs affect their therapeutic effects on retinal degeneration remains unknown.

Senescence-accelerated mice (SAM) are a range of congenital evolution from the AKR/J strain [4]. SAMR1 mice demonstrate normal aging process, while SAMP6 mice exhibit rapidly developing bone progeria within a few months after birth [5]. We have previously established that BMMSCs from SAMP6 mice show functional impairments in vitro, compared to their SAMR1 counterparts [6,7]. The retinal phenotypes of SAMR1 and SAMP6 mice have not yet been evaluated.

In this study, we aimed to explore whether bone progeria affect therapeutic effects of BMMSCs on retinal degeneration. To address this issue, we applied SAMR1 mice, SAMP6 mice and a retinal degeneration mice model induced by N-methyl-N-nitrosourea (MNU), a DNA alkylating agent [8], as we previously used [9]. And we found that bone progeria diminished the therapeutic effects of BMMSC on retinal degeneration.

Section snippets

Animals

All experiments were conducted following the Guidelines of Intramural Animal Use and Care Committee of the Xi’an Jiaotong University and the ARRIVE guidelines. 4 and 6 months old SAMP6 and SAMR1 mice were purchased from the Council for SAM Research of Kyoto University, Japan. For RP modeling, 40 mg/kg MNU (Sigma, USA) was intraperitoneally injected to C57BL/6J mice. 6 h later, 1 μl BMMSC (1 × 107/ml) [10] were injected into the vitreous chambers [11]. The visual function detected by

Months old SAMP6 mice demonstrated retinal degeneration

SAMP6 mice have previously been documented as a premature bone aging model [16]. To explore the potential retinal temporal changes, 4 months and 6 months old SAMP6 mice were analyzed respectively compared to the age-matched SAMR1 mice. H&E staining and ERG analysis showed that there were no significant morphological and functional differences between SAMP6 and SAMR1 retinas at 4 months old (Fig 1A∼D). Nevertheless, H&E staining displayed that the outer nucleus layers (ONL) of 6-month old SAMP6

Discussion

Bone aging brings about degenerative skeletal diseases such as primary osteoporosis and osteoarthritis, meanwhile also impairing BMMSCs as important pathogenesis [17]. Studies have shown that MSCT have significant protective effects on retinal degenerative diseases [18], but whether senescence of MSC diminishes the therapeutic efficacy remains unknown. In this study, we have discovered that retina of 6 months old SAMP6 mice underwent premature degeneration, and BMMSCs from SAMP6 mice

Funding information

This work was supported by the National Natural Science Foundation of China (81870676), the Postdoctoral Innovative Talents Support Program of China (BX20190380), the Young Elite Scientist Sponsorship Program by CAST of China (2019QNRC001 to B.D.S.), and the General Program of China Postdoctoral Science Foundation (2019M663986).

Declaration of competing interest

The authors have declared that no competing interest exists.

References (31)

  • B. Sui et al.

    Mesenchymal progenitors in osteopenias of diverse pathologies: differential characteristics in the common shift from osteoblastogenesis to adipogenesis

    Sci. Rep.

    (2016)
  • Y.-J. Lv et al.

    Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice

    Theranostics

    (2018)
  • C.B. Hu et al.

    NDRG2 suppression as a molecular hallmark of photoreceptor-specific cell death in the mouse retina

    Cell Death Discov.

    (2018)
  • W. Su et al.

    microRNA-21a-5p/PDCD4 axis regulates mesenchymal stem cell-induced neuroprotection in acute glaucoma

    J. Mol. Cell Biol.

    (2017)
  • B. Mead et al.

    Bone marrow-derived mesenchymal stem cells-derived exosomes promote survival of retinal ganglion cells through miRNA-dependent mechanisms

    Stem Cells Transl. Med.

    (2017)
  • Cited by (4)

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    These authors contributed equally to this work.

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