• Biomolecules & Therapeutics
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• v.28 no.3
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• pp.240-249
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• 2020

Despite the therapeutic effect of mesenchymal stem cells (MSCs) in ischemic diseases, pathophysiological conditions, including hypoxia, limited nutrient availability, and oxidative stress restrict their potential. To address this issue, we investigated the effect of melatonin on the bioactivities of MSCs. Treatment of MSCs with melatonin increased the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Melatonin treatment enhanced mitochondrial oxidative phosphorylation in MSCs in a PGC-1α-dependent manner. Melatonin-mediated PGC-1α expression enhanced the proliferative potential of MSCs through regulation of cell cycle-associated protein activity. In addition, melatonin promoted the angiogenic ability of MSCs, including migration and invasion abilities and secretion of angiogenic cytokines by increasing PGC-1α expression. In a murine hindlimb ischemia model, the survival of transplanted melatonin-treated MSCs was significantly increased in the ischemic tissues, resulting in improvement of functional recovery, such as blood perfusion, limb salvage, neovascularization, and protection against necrosis and fibrosis. These findings indicate that the therapeutic effect of melatonin-treated MSCs in ischemic diseases is mediated via regulation of PGC-1α level. This study suggests that melatonin-induced PGC-1α might serve as a novel target for MSC-based therapy of ischemic diseases, and melatonin-treated MSCs could be used as an effective cell-based therapeutic option for patients with ischemic diseases.

• Journal of Microbiology and Biotechnology
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• v.17 no.7
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• pp.1113-1119
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• 2007

Human bone marrow-derived mesenchymal stem cells (hBMMSCs) must differentiate into osteogenic cells to allow for successful bone regeneration. In this study, we investigated the effects of different combinations of three soluble osteogenic differentiation-inducing factors [L-ascorbic acid (AC), ${\beta}$-glycerophosphate (${\beta}G$), and bone morphogenic protein-2 (BMP-2)] and the presence of a hydroxyapatite (HA) substrate on hBMMSC osteogenic differentiation in vitro. hBMMSCs were cultured in medium containing various combinations of the soluble factors on culture plates with or without HA coating. After 7 days of culture, alkaline phosphatase (ALP) activity, calcium deposition, and osteoprotegerin (OPG) and osteopontin (OPN) expression were measured. The effects of individual and combined factors were evaluated using a factorial analysis method. BMP-2 predominantly affected expression of early markers of osteogenic differentiation (ALP and OPG). HA had the highest positive effect on OPN expression and calcium deposition. The interaction between AC, ${\beta}G$, and HA had the second highest positive effect on ALP activity.

• Clinical and Experimental Reproductive Medicine
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• v.45 no.2
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• pp.75-81
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• 2018

Objective: Recapitulation of the spermatogenesis process in vitro is a tool for studying the biology of germ cells, and may lead to promising therapeutic strategies in the future. In this study, we attempted to transdifferentiate Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) into male germ cells using all-trans retinoic acid and Sertoli cell-conditioned medium. Methods: Human WJ-MSCs were propagated by the explant culture method, and cells at the second passage were induced with differentiation medium containing all-trans retinoic acid for 2 weeks. Putative germ cells were cultured with Sertoli cell-conditioned medium at $36^{\circ}C$ for 3 more weeks. Results: The gene expression profile was consistent with the stage-specific development of germ cells. The expression of Oct4 and Plzf (early germ cell markers) was diminished, while Stra8 (a premeiotic marker), Scp3 (a meiotic marker), and Acr and Prm1 (postmeiotic markers) were upregulated during the induction period. In morphological studies, approximately 5% of the cells were secondary spermatocytes that had completed two stages of acrosome formation (the Golgi phase and the cap phase). A few spermatid-like cells that had undergone the initial stage of tail formation were also noted. Conclusion: Human WJ-MSCs can be transdifferentiated into more advanced stages of germ cells by a simple two-step induction protocol using retinoic acid and Sertoli cell-conditioned medium.

• Archives of Craniofacial Surgery
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• v.21 no.1
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• pp.58-63
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• 2020

Spindle cell squamous cell carcinoma (SpSCC) is a biphasic tumor composed of squamous cell epithelial and spindle cell mesenchymal components, both of which are malignant. Cutaneous SpSCC can cause diagnostic and therapeutic difficulties because of its rarity, heterogeneity, morphological similarity to other cutaneous spindle cell neoplasms, and uncertain pathogenesis and prognosis, particularly when the squamous cell carcinoma component is minimal or missing. Intransit metastasis and satellite lesion (satellitosis) constitute a spectrum of non-nodal regional metastases. Here the author reports the first known case of cutaneous SpSCC presenting with intransit metastases and a satellite lesion, which were exceptionally aggressive. A 77-year-old female patient presented with a 3×3×0.5 cm mass on her right cheek. Despite wide excision and postoperative radiation, the patient resulted in local recurrence and multiple distant metastases within 3 months. If many high-risk factors-particularly satellitosis and in-transit metastases are observed in a tumor with epithelial to mesenchymal transition, then further wide excision and adjuvant chemoradiation should be considered early in the treatment process. A multidisciplinary approach could be the key to cure the most aggressive malignancies of the skin, as in other organs.

• IMMUNE NETWORK
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• v.14 no.2
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• pp.81-88
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• 2014

Mesenchymal stem cells (MSCs) are present in diverse tissues and organs, including bone marrow, umbilical cord, adipose tissue, and placenta. MSCs can expand easily in vitro and have regenerative stem cell properties and potent immunoregulatory activity. They inhibit the functions of dendritic cells, B cells, and T cells, but enhance those of regulatory T cells by producing immunoregulatory molecules such as transforming growth factor-${\beta}$, hepatic growth factors, prostaglandin $E_2$, interleukin-10, indolamine 2,3-dioxygenase, nitric oxide, heme oxygenase-1, and human leukocyte antigen-G. These properties make MSCs promising therapeutic candidates for the treatment of autoimmune diseases. Here, we review the preclinical studies of MSCs in animal models for systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, and experimental autoimmune encephalomyelitis, and summarize the underlying immunoregulatory mechanisms.

• Biomedical Science Letters
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• v.15 no.4
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• pp.265-272
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• 2009

Recently, mesenchymal stem cells (MSCs) began to be utilized as a vehicle for ex vivo gene therapy based on their plasticity. Effective and safe transfection of therapeutic genes is a critical step for genetic modification of MSCs. Therefore, optimization of in vitro gene delivery into MSCs is essential to provide genetically modified stem cells. In this study, various cationic liposomes, O,O'-dimyristyl-N-lysyl aspartate (DMKD), DMKD/cholesterol, O,O'-dimyristyl-N-lysyl glutamate (DMKE), DMKE/cholesterol, and N-[1-(2,3-dioleoyloxy)]-N,N,N-trimethylammonium propane methyl sulfate (DOTAP)/cholesterol, were mixed with plasmid DNA encoding luciferase (pAAV-CMV-Luc) at varied ratios, and then used for transfection to MSCs under varied conditions. The MSCs were also transfected by electroporation under varied conditions, such as voltage, pulse length, and pulse interval. According to the experimental results, electroporation-mediated transfection was more efficient than cationic liposome-mediated transfection. The best MSC transfection was induced by electroporation 3 times pulses for 2 ms at 200 V with 10 seconds of a pulse interval.

• BMB Reports
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• v.48 no.8
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• pp.427-428
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• 2015

Despite high interests on microenvironmental regulation of leukemic cells, little is known for bone marrow (BM) niche in leukemia patients. Our recent study on BMs of acute myeloid leukemia (AML) patients showed that the mesenchymal stromal cells (MSCs) are altered during leukemic conditions in a clinical course-dependent manner. Leukemic blasts caused reprogramming of transcriptomes in MSCs and remodeling of niche cross-talk, selectively suppressing normal primitive hematopoietic cells while supporting leukemogenesis and chemo-resistance. Notably, differences in BM stromal remodeling were correlated to heterogeneity in subsequent clinical courses of AML, i.e., low numbers of mesenchymal progenitors at initial diagnosis were correlated to complete remission for 5-8 years, and high contents of mesenchymal progenitor or MSCs correlated to early or late relapse, respectively. Thus, stromal remodeling by leukemic cell is an intrinsic part of leukemogenesis that can contribute to the clonal dominance of leukemic cells over normal hematopoietic cells, and can serve as a biomarker for prediction of prognosis. [BMB Reports 2015; 48(8): 427-428]

• Clinical and Experimental Pediatrics
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• v.57 no.6
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• pp.251-256
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• 2014

Severe intraventricular hemorrhaging (IVH) in premature infants and subsequent posthemorrhagic hydrocephalus (PHH) causes significant mortality and life-long neurological complications, including seizures, cerebral palsy, and developmental retardation. However, there are currently no effective therapies for neonatal IVH. The pathogenesis of PHH has been mainly explained by inflammation within the subarachnoid spaces due to the hemolysis of extravasated blood after IVH. Obliterative arachnoiditis, induced by inflammatory responses, impairs cerebrospinal fluid (CSF) resorption and subsequently leads to the development of PHH with ensuing brain damage. Increasing evidence has demonstrated potent immunomodulating abilities of mesenchymal stem cells (MSCs) in various brain injury models. Recent reports of MSC transplantation in an IVH model of newborn rats demonstrated that intraventricular transplantation of MSCs downregulated the inflammatory cytokines in CSF and attenuated progressive PHH. In addition, MSC transplantation mitigated the brain damages that ensue after IVH and PHH, including reactive gliosis, cell death, delayed myelination, and impaired behavioral functions. These findings suggest that MSCs are promising therapeutic agents for neuroprotection in preterm infants with severe IVH.

• Toxicological Research
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• v.26 no.4
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• pp.245-252
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• 2010

Epithelial-mesenchymal transition (EMT) is a complex process in which epithelial cells acquire the characteristics of invasive mesenchymal cells. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Several oncogenic pathways such as transforming growth factor (TGF)-$\beta$, Wnt, and Notch signaling pathways, have been shown to induce EMT. These pathways have activated transcription factors including Snail, Slug, and the ZEB family which work as transcriptional repressors of E-cadherin, thereby making epithelial cells motile and resistant to apoptosis. Mounting evidence shows that EMT is associated with cell invasion and tumor progression. In this review, we summarize the characteristic features of EMT, pathways leading to EMT, and the role of EMT in cell invasion. Three topics are addressed in this review: (1) Definition of EMT, (2) Signaling pathways leading to EMT, (3) Role of EMT in cell invasion. Understanding the role of EMT in cell invasion will provide valuable information for establishing strategies to develop anti-metastatic therapeutics which modulate malignant cellular processes mediated by EMT.

• Toxicological Research
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• v.26 no.1
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• pp.15-19
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• 2010

Mesenchymal stem cells (MSCs) have greater potential for immediate clinical and toxicological applications, due to their ability to self-renew, proliferate, and differentiate into a variety of cell types. To identify novel candidate genes that were specifically expressed during transdifferentiation of human MSCs to neuronal cells, we performed a differential expression analysis with random priming approach using annealing control primer-based differential display reverse transcription-polymerase chain reaction approach. We identified genes for acyl-CoA thioesterase, tissue inhibitor of metalloproteinases-1, brain glycogen phosphorylase, ubiquitin C-terminal hydrolase and aldehyde reductase were up-regualted, whereas genes for transgelin and heparan sulfate proteoglycan were down-regulated in MSC-derived neurons. These differentially expressed genes may have potential role in regulation of neurogenesis. This study could be applied to environmental toxicology in the field of testing the toxicity of a chemical or a physical agent.