Adipose‐derived stem cells improve erectile function partially through the secretion of <scp>IGF</scp>‐1, <scp>bFGF</scp>, and <scp>VEGF</scp> in aged rats

Yang, Jun; Zhang, Y.; Zang, Guanghui; Wang, T.; Yu, Zhe; Wang, S.; Tang, Zhe; Liu, J.

doi:10.1111/andr.12483

Cited by 61 publications

(49 citation statements)

References 49 publications

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“…Volatile O 2 − is produced during cellular respiration by the mitochondria and NOX enzymes during tissue inflammation; O 2 − is eliminated by SOD which catalyzes its conversion to H 2 O 2 . Antioxidant effects of MSC treatments have been associated with enhanced SOD activity or the expression of SODs in models of aging, age‐related erectile dysfunction, chemotherapy‐induced pulmonary fibrosis or gonadotoxicity colitis, pancreatitis, septic lung injury, arthritis, hepatotoxicity and hepatic ischemia reperfusion injury, Alzheimer's disease, and ovarian autografts 33,34,37,38,43,50,62‐70 . MSCs secrete all isoforms of SOD including SOD1 and SOD2, which are archetypically not released extracellularly 33,59,71,72 .…”

Section: Antioxidative Mechanisms Of Mscsmentioning

confidence: 99%

The emerging antioxidant paradigm of mesenchymal stem cell therapy

Stavely

Nurgali

2020

Stem Cells Translational Medicine

146

101

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Mesenchymal stem cells (multipotent stromal cells; MSCs) have been under investigation for the treatment of diverse diseases, with many promising outcomes achieved in animal models and clinical trials. The biological activity of MSC therapies has not been fully resolved which is critical to rationalizing their use and developing strategies to enhance treatment efficacy. Different paradigms have been constructed to explain their mechanism of action, including tissue regeneration, trophic/anti‐inflammatory secretion, and immunomodulation. MSCs rarely engraft and differentiate into other cell types after in vivo administration. Furthermore, it is equivocal whether MSCs function via the secretion of many peptide/protein ligands as their therapeutic properties are observed across xenogeneic barriers, which is suggestive of mechanisms involving mediators conserved between species. Oxidative stress is concomitant with cellular injury, inflammation, and dysregulated metabolism which are involved in many pathologies. Growing evidence supports that MSCs exert antioxidant properties in a variety of animal models of disease, which may explain their cytoprotective and anti‐inflammatory properties. In this review, evidence of the antioxidant effects of MSCs in in vivo and in vitro models is explored and potential mechanisms of these effects are discussed. These include direct scavenging of free radicals, promoting endogenous antioxidant defenses, immunomodulation via reactive oxygen species suppression, altering mitochondrial bioenergetics, and donating functional mitochondria to damaged cells. Modulation of the redox environment and oxidative stress by MSCs can mediate their anti‐inflammatory and cytoprotective properties and may offer an explanation to the diversity in disease models treatable by MSCs and how these mechanisms may be conserved between species.

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Section: Antioxidative Mechanisms Of Mscsmentioning

confidence: 99%

The emerging antioxidant paradigm of mesenchymal stem cell therapy

Stavely

Nurgali

2020

Stem Cells Translational Medicine

146

101

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“…Kinins contribute to the reduction of oxidative stress by increasing the synthesis of nitric oxide (NO) and prostaglandin (PGs) (Kayashima et al, 2012). Several studies have established that oxidative stress plays an important role in the pathophysiological process of erectile dysfunction, and previously we showed that the levels oxidative stress in aged rats were significantly higher than in young rats (Yang et al, 2018). Increasing oxidative stress may drive the PI3K/AKT/ mTOR signaling pathway, resulting in the activation of mTOR.…”

Section: Discussionmentioning

confidence: 99%

Human tissue kallikrein 1 ameliorates erectile function via modulation of macroautophagy in aged transgenic rats

et al. 2018

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Previously, we have demonstrated that human tissue kallikrein 1 (hKLK1) improves age-related erectile dysfunction (ED). Autophagy has been implicated in age-related diseases, including ED. However, the molecular mechanisms underlying hKLK1-mediated amelioration of age-related ED via regulation of autophagy remains unknown. To explore the potential mechanism, male wild-type Sprague-Dawley rats (WTR) and transgenic rats harboring human KLK1 (TGR) were bred till 4 or 18 months of age and divided into three groups: young WTR (yWTR) as the control group, aged WTR (aWTR) group, and aged TGR (aTGR) group. The erectile function of each rat was evaluated using cavernous nerve electrostimulation. The ratio of intracavernous pressure/mean arterial pressure (ICP/MAP) and total ICP were also measured. Western blotting, immunohistochemistry, and transmission electron microscopy were performed to detect the levels of autophagy. The expression levels of related signaling pathways were determined by western blotting and immunohistochemistry. We found that hKLK1 improved the impaired erectile function of aged rats. Compared to the yWTR and aTGR groups, the aWTR group showed reduced smooth muscle/collagen ratio, fewer autophagosomes, and lower expression of Beclin 1 and LC3-II, which indicate impaired smooth muscle function and low level of autophagy in the smooth muscle cells. Moreover, the PI3K/Akt/mTOR signaling pathway, which is considered to be a negative regulator of autophagy, was upregulated in the aWTR group. hKLK1 may partially restore erectile function in aged transgenic rats by upregulating protective autophagy via the PI3K/Akt/mTOR pathway. These observations indicate that hKLK1 is a potential gene therapy candidate for age-related ED.

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“…We have con rmed that the BM-MSCs modi ed with shIGFBP-3 still retain their original characteristics, such as multidirectional differentiation potential and proliferation capacity in vitro. Producing some bioactivity factors may contribute to the therapeutic effects in vivo [28]. A paracrine action rather than the differentiation of stems cells may play a major role in the e cacy of stem cell transplanltion.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Yang. et al [28] revealed that ADSCs can improve erectile function through the secretion of cavernous IGF-1, bFGF, and VEGF in old rats. This study indicated that BM-MSCs alone, especially BM-MSCs modi ed with shRNA targeting IGFBP-3 treatment can improve aging-related ED partially owing to the secretion of IGF-1 and VEGF.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Modified With Short Hairpin RNA (shRNA) Constructs Targeting Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Improve Erectile Dysfunction in old Rats

Pu¹,

Zhang²,

Zhou³

et al. 2020

Preprint

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Background: We have confirmed that injection of vector-based short hairpin RNA (shRNA) constructs targeting insulin-like growth factor binding protein-3 (IGFBP-3) in penis in old rat can improve erectile function. The aim of this study is to further determine the feasibility of bone marrowe derived mesenchymal stem cells (BM-MSCs) genetically modified with shRNA constructs targeting IGFBP-3 on improving erectile function in the aged rat. Methods: 40 old (24 months) male rats were randomized divided into 4 groups: PBS-only, BM-MSC treatment and LV3-shIGFBP-3 engineered BM-MSC treatment group (n=10/group).Ten 5-month-old rats were used as the young group. Four weeks after transplantation, the erectile function was assessed by cavernosal nerve stimulation. The percent of smooth muscle in corpus cavernosum was evaluated by masson’s trichrome staining. IGFBP-3 expression was estimated by Western blot. The cavernous insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) levels were analyzed after transplantation. Apoptosis in corpus cavernosum was measured using TUNEL and the activity of nitric oxide synthase (NOS) and concentration of guanosine 3’, 5’-cyclic-monophosphates (cGMP) in penile tissue were also analyzed. Results: Four weeks after intracavernous injection, BM-MSCs alone, especially LV3-shIGFBP-3 engineered BM-MSCs treatment rats had improvements in erectile function (p<0.05). The percentage of cavernosal smooth muscle was increased in BM-MSCs and LV3-shIGFBP-3 engineered BM-MSCs treatment group. IGFBP-3 protein expression was decreased obviously after injection of LV3-shIGFBP-3 engineered BM-MSCs. In addition, significant lower IGFBP-3 expression was associated with increased IGF-1 expression in LV3-shIGFBP-3 engineered BM-MSCs treatment rats although higher IGF-1 and VEGF concentrations were all determined after transplantation with BM-MSCs alone or BM-MSCs modified with LV3-shIGFBP-3. Lower levels of the apoptosis were also observed in the BM-MSCs and LV3-shIGFBP-3 engineered BM-MSCs treatment group. NOS activities and cGMP concentrations were also significantly increased after transplantation. Conclusions: These findings demonstrate that BM-MSCs alone or genetically modified with LV3-shIGFBP-3 can improve diminished erectile responses in the aged rat partially by increasing the smooth muscle integrity, increasing secretion of IGF-1 and VEGF, inhibiting apoptosis and increasing the NOS activity and cGMP accumulation.

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Adipose‐derived stem cells improve erectile function partially through the secretion of IGF‐1, bFGF, and VEGF in aged rats

Cited by 61 publications

References 49 publications

The emerging antioxidant paradigm of mesenchymal stem cell therapy

The emerging antioxidant paradigm of mesenchymal stem cell therapy

Human tissue kallikrein 1 ameliorates erectile function via modulation of macroautophagy in aged transgenic rats

Mesenchymal Stem Cells Modified With Short Hairpin RNA (shRNA) Constructs Targeting Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Improve Erectile Dysfunction in old Rats

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