Background: Radical hysterectomy (RH) is a type of radical surgery for cervical cancer. Urinary dysfunction due to RH worsens postoperative quality of life of patients with cervical cancer. ...Nerve-sparing RH (NSRH) technique has been used as an effective means to conserve urinary function. However, few reports have examine long-term outcomes after NSRH. This study describes the details and long-term outcomes of our nerve-sparing technique. Methods: Sixty-one patients underwent radical hysterectomy in a 5-year period during which nerve-sparing technique was introduced; of these, 31 patients underwent NSRH and 30 underwent conventional RH. We retrospectively examined their medical records and compared postoperative urinary function and treatment outcomes between these two groups. Results: The median time required for urinary residual volume to fall to ≤50 mL after removal of the urinary catheter was 6 days (range, 2-20 days) in the NSRH group and 13.5 days (range, 3-46 days) in the RH group. The results were significantly better in the NSRH group (p < 0.05). The mean follow-up period was 2456.3 days (range, 48-4,213 days). Analysis of curability revealed no significant difference between the two groups in local recurrence or long-term survival rates. The 5-year survival rate was 0.861 in the NSRH group and 0.782 in the RH group; the 10-year survival rate was 0.861 in the NSRH group and 0.679 in the RH group. Conclusions: NSRH significantly improved postoperative urinary function without worsening local recurrence rates or long-term outcomes.
Loading is indispensable for the growth, development, and maintenance of joint tissues, including mandibular condylar cartilage, but excessive loading or reduced host adaptive capacity can ...considerably damage the temporomandibular joint (TMJ), leading to temporomandibular joint osteoarthritis (TMJ-OA). TMJ-OA, associated with other pathological conditions and aging processes, is a highly degenerative disease affecting the articular cartilage. Many treatment modalities for TMJ-OA have been developed. Traditional clinical treatment includes mainly nonsurgical options, such as occlusal splints. However, non-invasive therapy does not achieve joint tissue repair and regeneration. Growing evidence suggests that low-intensity pulsed ultrasound (LIPUS) accelerates bone fracture healing and regeneration, as well as having extraordinary effects in terms of soft tissue repair and regeneration. The latter have received much attention, and various studies have been performed to evaluate the potential role of LIPUS in tissue regeneration including that applied to articular cartilage. The present article provides an overview of the status of LIPUS stimulation used to prevent the onset and progression of TMJ-OA and enhance the tissue regeneration of mandibular condylar cartilage. The etiology and management of TMJ-OA are explained briefly, animal models of TMJ-OA are described, and the effectiveness of LIPUS on cell metabolism and tissue regeneration in the TMJ is discussed.
•Intranasal administration of SHED-CM improves cognition in a mouse model of AD.•SHED-CM converts the pro-inflammatory AD environment to an anti-inflammatory one.•SHED-CM induces the accumulation of ...M2 microglia in the mouse AD brain.•SHEDs secrete multiple factors beneficial for the treatment of AD.
Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by a decline in cognitive abilities and the appearance of β-amyloid plaques in the brain. Although the pathogenic mechanisms associated with AD are not fully understood, activated microglia releasing various neurotoxic factors, including pro-inflammatory cytokines and oxidative stress mediators, appear to play major roles. Here, we investigated the therapeutic benefits of a serum-free conditioned medium (CM) derived from the stem cells of human exfoliated deciduous teeth (SHEDs) in a mouse model of AD. The intranasal administration of SHEDs in these mice resulted in substantially improved cognitive function. SHED-CM contained factors involved in multiple neuroregenerative mechanisms, such as neuroprotection, axonal elongation, neurotransmission, the suppression of inflammation, and microglial regulation. Notably, SHED-CM attenuated the pro-inflammatory responses induced by β-amyloid plaques, and generated an anti-inflammatory/tissue-regenerating environment, which was accompanied by the induction of anti-inflammatory M2-like microglia. Our data suggest that SHED-CM may provide significant therapeutic benefits for AD.
Stem cells from human exfoliated deciduous teeth (SHEDs) can regenerate various tissues. We investigated the impact of SHED-conditioned medium (SHED-CM) on myocardial injury in a mouse model of ...ischemia-reperfusion (I/R). Wild-type (WT) mice were subjected to myocardial ischemia followed by reperfusion. SHED-CM was intravenously injected at 5 min after reperfusion. Administration of SHED-CM reduced myocardial infarct size as well as decreased apoptosis and inflammatory cytokine levels, such as TNF-α, IL-6, and IL-β, in the myocardium following I/R. In cultured cardiac myocytes, SHED-CM significantly suppressed apoptosis under hypoxia/serum-deprivation and reduced LPS-induced expression of pro-inflammatory genes. Furthermore, anti-apoptotic action of SHED-CM was stronger than bone marrow-derived stem cell (BMSC)-CM or adipose-derived stem cell (ADSC)-CM in cardiac myocytes. SHED-CM contains a higher concentration of hepatocyte growth factor (HGF) than BMSC-CM and ADSC-CM, and neutralization of HGF attenuated the inhibitory actions of SHED-CM on apoptosis in cardiac myocytes. Finally, WT mice were intravenously treated with an HGF-depleted SHED-CM, followed by myocardial I/R. HGF depletion significantly attenuated the inhibitory actions of SHED-CM on myocardial infarct size and apoptosis after I/R. SHED-CM protects the heart from acute ischemic injury because it suppresses inflammation and apoptosis. SHED-CM could be a useful treatment option for acute myocardial infarction.
Multiple sclerosis (MS) is a major neuroinflammatory demyelinating disease of the CNS. Current MS treatments, including immunomodulators and immunosuppressants, do not result in complete remission. ...Stem cells from human exfoliated deciduous teeth (SHEDs) are mesenchymal stem cells derived from dental pulp. Both SHED and SHED-conditioned medium (SHED-CM) exhibit immunomodulatory and regenerative activities and have the potential to treat various diseases. In this study, we investigated the efficacy of SHED-CM in treating experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. EAE mice treated with a single injection of SHED-CM exhibited significantly improved disease scores, reduced demyelination and axonal injury, and reduced inflammatory cell infiltration and proinflammatory cytokine expression in the spinal cord, which was associated with a shift in the microglia/macrophage phenotype from M1 to M2. SHED-CM also inhibited the proliferation of myelin oligodendrocyte glycoprotein-specific CD4(+) T cells, as well as their production of proinflammatory cytokines in vitro. Treatment of EAE mice with the secreted ectodomain of sialic acid-binding Ig-like lectin-9, a major component of SHED-CM, recapitulated the effects of SHED-CM treatment. Our data suggest that SHED-CM and secreted ectodomain of sialic acid-binding Ig-like lectin-9 may be novel therapeutic treatments for autoimmune diseases, such as MS.
Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We ...examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α, Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.
Perinatal hypoxia-ischemia (HI) has high rates of neurological deficits and mortality. So far, no effective treatment for HI brain injury has been developed. In this study, we investigated the ...therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) for the treatment of neonatal HI brain injury.
Unilateral HI was induced in postnatal day 5 (P5) mice. Twenty-four hours later, SHED, human skin fibroblasts, or serum-free conditioned medium derived from these cells was injected into the injured brain. The effects of cell transplantation or conditioned medium injection on the animals' neurological and pathophysiological recovery were evaluated.
Transplanted SHED, but not fibroblasts, significantly reduced the HI-induced brain-tissue loss and improved neurological function. SHED also improved the survival of the HI mice. The engrafted SHED rarely differentiated into neural lineages; however, their transplantation inhibited the expression of proinflammatory cytokines, increased the expression of anti-inflammatory ones, and significantly reduced apoptosis. Notably, the intracerebral administration of SHED-conditioned medium also significantly improved the neurological outcome, inhibited apoptosis, and reduced tissue loss.
SHED transplantation into the HI-injured brain resulted in remarkable neurological and pathophysiological recovery. Our findings indicate that paracrine factors derived from SHED support a neuroprotective microenvironment in the HI brain. SHED graft and SHED-conditioned medium may provide a novel neuroprotective therapy for HI.
Abstract Distraction osteogenesis (DO) successfully induces large-scale skeletal tissue regeneration, but it involves an undesirably long treatment period. A high-speed DO mouse model (H-DO) with a ...distraction speed twice that of a control DO model failed to generate new bone callus in the distraction gap. Here we demonstrate that the local administration of serum-free conditioned medium from human mesenchymal stem cells (MSC-CM) accelerated callus formation in the mouse H-DO model. Secretomic analysis identified factors contained in MSC-CM that recruit murine bone marrow stromal cells (mBMSCs) and endothelial cells/endothelial progenitor cells (EC/EPCs), inhibit inflammation and apoptosis, and promote osteoblast differentiation, angiogenesis, and cell proliferation. Functional assays identified MCP-1/-3 and IL-3/-6 as essential factors in recruiting mBMSCs and EC/EPCs. IL-3/-6 also enhanced the osteogenic differentiation of mBMSCs. MSC-CM that had been depleted of MCP-1/-3 failed to recruit mBMSCs, and consequently failed to promote callus formation. Taken together, our data suggest that MSCs produce a broad repertoire of trophic factors with tissue-regenerative activities that accelerate healing in the DO process.
Peripheral nerves (PNs) exhibit remarkable self‐repairing reparative activity after a simple crush or cut injury. However, the neuronal transection involving a nerve gap overwhelms their repairing ...activity and causes persistent paralysis. Here, we show that an implantation of the serum‐free conditioned medium from stem cells from human exfoliated deciduous teeth (SHED‐CM) immersed in a collagen sponge into the nerve gap formed by rat facial nerves transection restored the neurological function. In contrast, SHED‐CM specifically depleted of a set of anti‐inflammatory M2 macrophage inducers, monocyte chemoattractant protein‐1 (MCP‐1) and the secreted ectodomain of sialic acid‐binding Ig‐like lectin‐9 (sSiglec‐9) lost the ability to restore neurological function in this model. Notably, the combination of MCP‐1 and sSiglec‐9 induced the polarization of M2 macrophages in vitro, resulting in the expression of multiple trophic factors that enhanced proliferation, migration, and differentiation of Schwann cells, blood vessel formation, and nerve fiber extension. Furthermore, the implantation of a collagen graft containing MCP‐1/sSiglec‐9 into the nerve gap induced anti‐inflammatory M2 macrophage polarization, generated a Schwann‐cell bridge instead of fibrotic scar, induced axonal regrowth, and restored nerve function. The specific elimination of M2 macrophages by Mannosylated‐Clodrosome suppressed the MCP‐1/sSiglec‐9‐mediated neurological recovery. Taken together, our data suggest that MCP‐1/sSiglec‐9 regenerates PNs by inducing tissue‐repairing M2 macrophages and may provide therapeutic benefits for severe peripheral nerve injuries. Stem Cells 2017;35:641–653
Monocyte chemoattractant protein‐1 (MCP‐1) and sialic acid‐binding Ig‐like lectin‐9 (sSiglec‐9) secreted from dental pulp stem cells polarized bone marrow‐derived macrophages toward tissue reparative M2, which expressed multiple trophic factors that enhanced proliferation, migration, and differentiation of Schwann cells (SCs), blood vessel formation, and nerve fiber extension. Transection of facial nerve involving a nerve gap overwhelms their repairing activity, however MCP‐1/sSiglec‐9 treatment restored nerve function through the induction of M2 in the nerve gap. The M2 promoted recruitment of a number of de‐differentiated SCs, formation of a SC bridge and extension of the transected nerve fiber. Our study demonstrates the remarkable therapeutic benefits of the stem cell‐derived M2 inducers, MCP‐1 and sSiglec‐9, for regenerating severely injured peripheral nerves.
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