研究者詳細 - 森川　暁

論文 - 森川　暁

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Recurrent Spindle Cell Carcinoma Shows Features of Mesenchymal Stem Cells

Ouchi T., Morikawa S., Shibata S., Takahashi M., Yoshikawa M., Soma T., Miyashita H., Muraoka W., Kameyama K., Kawana H., Arima Y., Saya H., Okano H., Nakagawa T., Asoda S.

Journal of Dental Research （Journal of Dental Research） 97 （ 7 ） 779 - 786 2018年07月

ISSN 1544-0591

This study investigated a case of spindle cell carcinoma (SpCC) in tongue pathological lesions. The patient experienced a local recurrence and distant metastasis after surgical intervention. Although standard chemotherapy was administered, a granulomatous mass continued to develop. This aggressive growth led to survival of the tumor. Secondary debulking surgery was performed to improve the patient’s quality of life at the request of the patient. Using a tissue sample derived from the secondary debulking surgery, we performed an analysis of the tumor’s cell surface antigens, differentiation potential, metastatic ability, and inhibition potential by anticancer reagents. In vitro analysis revealed that the cell population grown under adherent culture conditions expressed the mesenchymal stem cell (MSC) markers CD73, CD90, and CD105. The cell line established from this SpCC contained colony-forming unit fibroblasts (CFU-Fs) and exhibited multipotent differentiation into several mesenchymal lineages, including bone, cartilage, and fat. The SpCC cells also displayed vigorous mobilization. These characteristics suggested that they had the differentiation potential of mesenchymal cells, especially MSCs, rather than that of epithelial cells. The surgical specimen analyzed in this study resisted the molecular target reagent cetuximab, which is an epidermal growth factor receptor inhibitor. This clinical insight revealed that chemotherapy-resistant SpCC cells have different characteristics compared to most other cancer cells, which are sensitive to cetuximab. Our cell death assay revealed that SpCC cell death was induced by the anticancer drug imatinib, which is known to inhibit protein tyrosine kinase activity of ABL, platelet-derived growth factor receptor α (PDGFRα), and KIT. Here, we report recurrent SpCC with characteristics of MSCs and potential for treatment with imatinib.

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Treatment of severe generalized chronic periodontitis in a patient with Behçet’s disease: A case report

Morikawa S., Ouchi T., Asoda S., Horie N., Tsunoda K., Kawana H., Nakagawa T.

Journal of International Medical Research （Journal of International Medical Research） 46 （ 5 ） 2037 - 2045 2018年05月

ISSN 1473-2300

Behçet’s disease is a systemic disorder of unknown etiology. It involves multiple organ systems and is characterized by recurring episodes of oral ulcers as well as ocular, genital, and skin lesions. Oral ulcers can affect tooth brushing and impair proper oral hygiene. As a result, a dental biofilm accumulates, and the condition of the teeth and periodontal tissue deteriorates. The aim of this case report is to highlight the efficacy of periodontal treatment for patients with Behçet’s disease. A 51-year-old man with Behçet’s disease presented with generalized severe periodontitis. After basic treatment of the periodontal tissues, periodontal surgery was performed at several sites with bony defects. However, the patient developed severe stomatitis in the oral mucosa and gingiva after periodontal surgery. Administration of the antimicrobial agent cefdinir had little effect on recovery; however, subsequent administration of sitafloxacin resulted in significant improvement of the stomatitis. This case demonstrates that periodontal therapy is very useful for alleviating the oral signs and symptoms of Behçet’s disease. Systemic antibiotic treatment with sitafloxacin (but not cefdinir) and mechanical debridement were effective in preventing the recurrence of aphthous ulcer outbreaks after periodontal surgery.

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Functional role of lacrimal gland fibroblasts in a mouse model of chronic graft-versus-host disease

Yamane M., Ogawa Y., Mukai S., Yaguchi S., Kamijuku H., Inaba T., Asai K., Morikawa S., Kawakami Y., Shimmura S., Tsubota K.

Cornea （Cornea） 37 （ 1 ） 102 - 108 2018年01月

ISSN 1536-4798

Purpose: This study aimed to clarify the mechanisms and assess the characteristics of the chronic graft-versus-host disease (cGVHD) fibrosis in the lacrimal gland (LG) of mice. Methods: Histopathology of LG tissues was examined by immunohistochemistry and electron microscopy. Cultured fibroblasts derived from the LG were analyzed by phase-contrast microscopy, immunocytochemistry, flow cytometry, proliferation assay, and invasion and migration assays. Results: Cultured murine LG fibroblasts in cGVHD were spindle-shaped and relatively small, whereas those from syngeneic controls were polygon-shaped and relatively large. Flow cytometric analysis showed that the LG fibroblasts in cGVHD had elevated HSP47 levels. The LG fibroblasts in cGVHD also showed increased expression of major histocompatibility complex class II. Furthermore, the proportion of Sca-1+PDGFR-a+ cells among the LG fibroblasts in cGVHD was considerably increased compared with controls. Cell counting kit-8 assays demonstrated that the LG fibroblasts in cGVHD were highly proliferative, and cell invasion assays indicated that they were highly invasive with high migration ability. Conclusions: LG fibroblasts in cGVHD can be aberrantly activated, thereby eliciting fibrosis by producing excessive extracellular matrix, leading to LG dysfunction in mice.

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The potential of enriched mesenchymal stem cells with neural crest cell phenotypes as a cell source for regenerative dentistry

Niibe, K., Zhang, M., Nakazawa, K., Morikawa, S., Nakagawa, T., Matsuzaki, Y. and Egusa, H.

Jpn Dent Sci Rev 53 （ 2 ） 25 - 33 2017年05月

ISSN 1882-7616

Effective regenerative treatments for periodontal tissue defects have recently been demonstrated using mesenchymal stromal/stem cells (MSCs). Furthermore, current bioengineering techniques have enabled de novo fabrication of tooth-perio dental units in mice. These cutting-edge technologies are expected to address unmet needs within regenerative dentistry. However, to achieve efficient and stable treatment outcomes, preparation of an appropriate stem cell source is essential. Many researchers are investigating the use of adult stem cells for regenerative dentistry; bone marrow-derived MSCs (BM-MSCs) are particularly promising and presently used clinically. However, current BM-MSC isolation techniques result in a heterogeneous, non-reproducible cell population because of a lack of identified distinct BM-MSC surface markers. Recently, specific subsets of cell surface markers for BM-MSCs have been reported in mice (PDGFRalpha(+) and Sca-1(+)) and humans (LNGFR(+), THY-1(+) and VCAM-1(+)), facilitating the isolation of unique enriched BM-MSCs (so-called "purified MSCs"). Notably, the enriched BM-MSC population contains neural crest-derived cells, which can differentiate into cells of neural crest- and mesenchymal lineages. In this review, characteristics of the enriched BM-MSCs are outlined with a focus on their potential application within future regenerative dentistry.

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Isolation of dental pulp stem cells with high osteogenic potential

Yasui, T., Mabuchi, Y., Morikawa, S., Onizawa, K., Akazawa, C., Nakagawa, T., Okano, H. and Matsuzaki, Y.

Inflamm Regen 37 （ April ） 8 2017年04月

ISSN 1880-9693

Dental pulp stem cells/progenitor cells (DPSCs) can be easily obtained and can have excellent proliferative and mineralization potentials. Therefore, many studies have investigated the isolation and bone formation of DPSCs. In most previous reports, human DPSCs were traditionally isolated by exploiting their ability to adhere to plastic tissue culture dishes. DPSCs isolated by plastic adherence are frequently contaminated by other cells, which limits the ability to investigate their basic biology and regenerative properties. Additionally, the proliferative and osteogenic potentials vary depending on the isolated cells. It is very difficult to obtain cells of a sufficient quality to elicit the required effect upon transplantation. Considering clinical applications, stem cells used for regenerative medicine need to be purified in order to increase the efficiency of bone regeneration, and a stable supply of these cells must be generated. Here, we review the purification of DPSCs and studies of cranio-maxillofacial bone regeneration using these cells. Additionally, we introduce the prospective isolation of DPSCs using specific cell surface markers: low-affinity nerve growth factor and thymocyte antigen 1.

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Applications of Mesenchymal Stem Cells and Neural Crest Cells in Craniofacial Skeletal Research

Morikawa, S., Ouchi, T., Shibata, S., Fujimura, T., Kawana, H., Okano, H. and Nakagawa, T.

Stem Cells Int 2016 2849879 2016年

ISSN 1687-966X

Craniofacial skeletal tissues are composed of tooth and bone, together with nerves and blood vessels. This composite material is mainly derived from neural crest cells (NCCs). The neural crest is transient embryonic tissue present during neural tube formation whose cells have high potential for migration and differentiation. Thus, NCCs are promising candidates for craniofacial tissue regeneration; however, the clinical application of NCCs is hindered by their limited accessibility. In contrast, mesenchymal stem cells (MSCs) are easily accessible in adults, have similar potential for self-renewal, and can differentiate into skeletal tissues, including bones and cartilage. Therefore, MSCs may represent good sources of stem cells for clinical use. MSCs are classically identified under adherent culture conditions, leading to contamination with other cell lineages. Previous studies have identified mouse- and human-specific MSC subsets using cell surface markers. Additionally, some studies have shown that a subset of MSCs is closely related to neural crest derivatives and endothelial cells. These MSCs may be promising candidates for regeneration of craniofacial tissues from the perspective of developmental fate. Here, we review the fundamental biology of MSCs in craniofacial research.

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Notch2 Signaling Regulates the Proliferation of Murine Bone Marrow-Derived Mesenchymal Stem/Stromal Cells via c-Myc Expression

Sato, Y., Mabuchi, Y., Miyamoto, K., Araki, D., Niibe, K., Houlihan, D. D., Morikawa, S., Nakagawa, T., Nakajima, T., Akazawa, C., Hori, S., Okano, H. and Matsuzaki, Y.

PLoS One 11 （ 11 ） e0165946 2016年

ISSN 1932-6203

Mesenchymal stem/stromal cells (MSCs) reside in the bone marrow and maintain their stemness under hypoxic conditions. However, the mechanism underlying the effects of hypoxia on MSCs remains to be elucidated. This study attempted to uncover the signaling pathway of MSC proliferation. Under low-oxygen culture conditions, MSCs maintained their proliferation and differentiation abilities for a long term. The Notch2 receptor was up-regulated in MSCs under hypoxic conditions. Notch2-knockdown (Notch2-KD) MSCs lost their cellular proliferation ability and showed reduced gene expression of hypoxia-inducible transcription factor (HIF)-1alpha, HIF-2alpha, and c-Myc. Overexpression of the c-Myc gene in Notch2-KD MSCs allowed the cells to regain their proliferation capacity. These results suggested that Notch2 signaling is linked to c-Myc expression and plays a key role in the regulation of MSC proliferation. Our findings provide important knowledge for elucidating the self-replication competence of MSCs in the bone marrow microenvironment.

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LNGFR(+)THY-1(+) human pluripotent stem cell-derived neural crest-like cells have the potential to develop into mesenchymal stem cells

Ouchi, T., Morikawa, S., Shibata, S., Fukuda, K., Okuno, H., Fujimura, T., Kuroda, T., Ohyama, M., Akamatsu, W., Nakagawa, T. and Okano, H.

Differentiation 92 （ 5 ） 270 - 280 2016年12月

ISSN 1432-0436

Mesenchymal stem cells (MSCs) are defined as non-hematopoietic, plastic-adherent, self-renewing cells that are capable of tri-lineage differentiation into bone, cartilage or fat in vitro. Thus, MSCs are promising candidates for cell-based medicine. However, classifications of MSCs have been defined retrospectively; moreover, this conventional criterion may be inaccurate due to contamination with other hematopoietic lineage cells. Human MSCs can be enriched by selection for LNGFR and THY-1, and this population may be analogous to murine PDGFRalpha(+)Sca-1(+) cells, which are developmentally derived from neural crest cells (NCCs). Murine NCCs were labeled by fluorescence, which provided definitive proof of neural crest lineage, however, technical considerations prevent the use of a similar approach to determine the origin of human LNGFR(+)THY-1(+) MSCs. To further clarify the origin of human MSCs, human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) were used in this study. Under culture conditions required for the induction of neural crest cells, human ESCs and iPSCs-derived cells highly expressed LNGFR and THY-1. These LNGFR(+)THY-1(+) neural crest-like cells, designated as LT-NCLCs, showed a strong potential to differentiate into both mesenchymal and neural crest lineages. LT-NCLCs proliferated to form colonies and actively migrated in response to serum concentration. Furthermore, we transplanted LT-NCLCs into chick embryos, and traced their potential for survival, migration and differentiation in the host environment. These results suggest that LNGFR(+)THY-1(+) cells identified following NCLC induction from ESCs/iPSCs shared similar potentials with multipotent MSCs.

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Purified Human Dental Pulp Stem Cells Promote Osteogenic Regeneration

Yasui, T., Mabuchi, Y., Toriumi, H., Ebine, T., Niibe, K., Houlihan, D. D., Morikawa, S., Onizawa, K., Kawana, H., Akazawa, C., Suzuki, N., Nakagawa, T., Okano, H. and Matsuzaki, Y.

J Dent Res 95 （ 2 ） 206 - 14 2016年02月

ISSN 1544-0591

Human dental pulp stem/progenitor cells (hDPSCs) are attractive candidates for regenerative therapy because they can be easily expanded to generate colony-forming unit-fibroblasts (CFU-Fs) on plastic and the large cell numbers required for transplantation. However, isolation based on adherence to plastic inevitably changes the surface marker expression and biological properties of the cells. Consequently, little is currently known about the original phenotypes of tissue precursor cells that give rise to plastic-adherent CFU-Fs. To better understand the in vivo functions and translational therapeutic potential of hDPSCs and other stem cells, selective cell markers must be identified in the progenitor cells. Here, we identified a dental pulp tissue-specific cell population based on the expression profiles of 2 cell-surface markers LNGFR (CD271) and THY-1 (CD90). Prospectively isolated, dental pulp-derived LNGFR(Low+)THY-1(High+) cells represent a highly enriched population of clonogenic cells--notably, the isolated cells exhibited long-term proliferation and multilineage differentiation potential in vitro. The cells also expressed known mesenchymal cell markers and promoted new bone formation to heal critical-size calvarial defects in vivo. These findings suggest that LNGFR(Low+)THY-1(High+) dental pulp-derived cells provide an excellent source of material for bone regenerative strategies.

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MHC-compatible bone marrow stromal/stem cells trigger fibrosis by activating host T cells in a scleroderma mouse model

Ogawa, Y., Morikawa, S., Okano, H., Mabuchi, Y., Suzuki, S., Yaguchi, T., Sato, Y., Mukai, S., Yaguchi, S., Inaba, T., Okamoto, S., Kawakami, Y., Tsubota, K., Matsuzaki, Y. and Shimmura, S.

Elife 5 e09394 2016年01月

ISSN 2050-084X

Fibrosis of organs is observed in systemic autoimmune disease. Using a scleroderma mouse, we show that transplantation of MHC compatible, minor antigen mismatched bone marrow stromal/stem cells (BMSCs) play a role in the pathogenesis of fibrosis. Removal of donor BMSCs rescued mice from disease. Freshly isolated PDGFRalpha(+) Sca-1(+) BMSCs expressed MHC class II following transplantation and activated host T cells. A decrease in FOXP3(+) CD25(+) Treg population was observed. T cells proliferated and secreted IL-6 when stimulated with mismatched BMSCs in vitro. Donor T cells were not involved in fibrosis because transplanting T cell-deficient RAG2 knock out mice bone marrow still caused disease. Once initially triggered by mismatched BMSCs, the autoimmune phenotype was not donor BMSC dependent as the phenotype was observed after effector T cells were adoptively transferred into naive syngeneic mice. Our data suggest that minor antigen mismatched BMSCs trigger systemic fibrosis in this autoimmune scleroderma model.

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CD34 and CD49f Double-Positive and Lineage Marker-Negative Cells Isolated from Human Myometrium Exhibit Stem Cell-Like Properties Involved in Pregnancy-Induced Uterine Remodeling

Ono, M., Kajitani, T., Uchida, H., Arase, T., Oda, H., Uchida, S., Ota, K., Nagashima, T., Masuda, H., Miyazaki, K., Asada, H., Hida, N., Mabuchi, Y., Morikawa, S., Ito, M., Bulun, S. E., Okano, H., Matsuzaki, Y., Yoshimura, Y. and Maruyama, T.

Biol Reprod 93 （ 2 ） 37 2015年08月

ISSN 1529-7268

Repeated and dramatic pregnancy-induced uterine enlargement and remodeling throughout reproductive life suggests the existence of uterine smooth muscle stem/progenitor cells. The aim of this study was to isolate and characterize stem/progenitor-like cells from human myometrium through identification of specific surface markers. We here identify CD49f and CD34 as markers to permit selection of the stem/progenitor cell-like population from human myometrium and show that human CD45(-) CD31(-) glycophorin A(-) and CD49f(+) CD34(+) myometrial cells exhibit stem cell-like properties. These include side population phenotypes, an undifferentiated status, high colony-forming ability, multilineage differentiation into smooth muscle cells, osteoblasts, adipocytes, and chondrocytes, and in vivo myometrial tissue reconstitution following xenotransplantation. Furthermore, CD45(-) CD31(-) glycophorin A(-) and CD49f(+) CD34(+) myometrial cells proliferate under hypoxic conditions in vitro and, compared with the untreated nonpregnant myometrium, show greater expansion in the estrogen-treated nonpregnant myometrium and further in the pregnant myometrium in mice upon xenotransplantation. These results suggest that the newly identified myometrial stem/progenitor-like cells influenced by hypoxia and sex steroids may participate in pregnancy-induced uterine enlargement and remodeling, providing novel insights into human myometrial physiology.

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Homeodomain transcription factor Meis1 is a critical regulator of adult bone marrow hematopoiesis

Ariki, R., Morikawa, S., Mabuchi, Y., Suzuki, S., Nakatake, M., Yoshioka, K., Hidano, S., Nakauchi, H., Matsuzaki, Y., Nakamura, T. and Goitsuka, R.

PLoS One 9 （ 2 ） e87646 2014年

ISSN 1932-6203

Hematopoietic stem cells in the bone marrow have the capacity to both self-renew and to generate all cells of the hematopoietic system. The balance of these two activities is controlled by hematopoietic stem cell-intrinsic regulatory mechanisms as well as extrinsic signals from the microenvironment. Here we demonstrate that Meis1, a TALE family homeodomain transcription factor involved in numerous embryonic developmental processes, is selectively expressed in hematopoietic stem/progenitor cells. Conditional Meis1 knockout in adult hematopoietic cells resulted in a significant reduction in the hematopoietic stem/progenitor cells. Suppression of hematopoiesis by Meis1 deletion appears to be caused by impaired self-renewal activity and reduced cellular quiescence of hematopoietic stem/progenitor cells in a cell autonomous manner, resulting in stem cell exhaustion and defective long-term hematopoiesis. Meis1 deficiency down-regulated a subset of Pbx1-dependent hematopoietic stem cell signature genes, suggesting a functional link between them in the maintenance of hematopoietic stem/progenitor cells. These results show the importance of Meis1 in adult hematopoiesis.

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LNGFR(+)THY-1(+)VCAM-1(hi+) cells reveal functionally distinct subpopulations in mesenchymal stem cells

Mabuchi, Y., Morikawa, S., Harada, S., Niibe, K., Suzuki, S., Renault-Mihara, F., Houlihan, D. D., Akazawa, C., Okano, H. and Matsuzaki, Y.

Stem Cell Reports 1 （ 2 ） 152 - 65 2013年

ISSN 2213-6711

Human mesenchymal stem cells (hMSCs), which conventionally are isolated based on their adherence to plastic, are heterogeneous and have poor growth and differentiation, limiting our ability to investigate their intrinsic characteristics. We report an improved prospective clonal isolation technique and reveal that the combination of three cell-surface markers (LNGFR, THY-1, and VCAM-1) allows for the selection of highly enriched clonogenic cells (one out of three isolated cells). Clonal characterization of LNGFR(+)THY-1(+) cells demonstrated cellular heterogeneity among the clones. Rapidly expanding clones (RECs) exhibited robust multilineage differentiation and self-renewal potency, whereas the other clones tended to acquire cellular senescence via P16INK4a and exhibited frequent genomic errors. Furthermore, RECs exhibited unique expression of VCAM-1 and higher cellular motility compared with the other clones. The combination marker LNGFR(+)THY-1(+)VCAM-1(hi+) (LTV) can be used selectively to isolate the most potent and genetically stable MSCs.

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Primary evaluation of induced pluripotent stem cells using flow cytometry

Araki, D., Kawamura, Y., Niibe, K., Suzuki, S., Morikawa, S., Mabuchi, Y., Nakagawa, T., Okano, H. and Matsuzaki, Y.

Inflammation and Regeneration 33 （ 1 ） 3 - 12 2013年01月

ISSN 1880-9693

マウス成体組織、間葉系幹細胞(MSC)および尻尾線維芽細胞からセンダイウイルスを用いてゲノム組込みのない人工多能性幹細胞(iPS細胞)を作成した。続いて、成体MSC由来のレトロウイルス誘導iPS細胞株および非組込みiPS細胞株から形成された二次ニューロスフェアに残存する未分化細胞を検出した。その結果、MSCからのみ組込みのないiPS細胞が得られた。しかし、非組込み法で得られたiPS細胞株の一部も未分化細胞を含んでいた。組込みのないiPS細胞のうち正しく分化しないものはフローサイトメトリーにて他のES/iPS細胞よりも高い側方散乱光(SSC)強度を示した。いくつかの体細胞由来iPS細胞は高いSSC強度を示し、これらの細胞は正常に分化しなかった。SSC強度の解析は個別のiPS細胞の評価に有効な手段である。

Isolation of mouse mesenchymal stem cells on the basis of expression of Sca-1 and PDGFR-alpha

Houlihan, D. D., Mabuchi, Y., Morikawa, S., Niibe, K., Araki, D., Suzuki, S., Okano, H. and Matsuzaki, Y.

Nat Protoc 7 （ 12 ） 2103 - 11 2012年12月

ISSN 1750-2799

Platelet-derived growth factor receptor alpha (PDGFR-alpha) and stem cell antigen 1 (Sca-1) have recently been identified as selective markers of mouse mesenchymal stem cells (MSCs). PDGFR-alpha(+)Sca-1(+) (PalphaS) MSCs have augmented growth potential and robust tri-lineage differentiation compared with standard culture-selected MSCs. In addition, the selective isolation of PalphaS MSCs avoids cellular contamination that can complicate other methods. Here we describe in detail our protocol to isolate PalphaS MSCs using flow cytometry. In brief, the tibia and femora are isolated and crushed using a pestle and mortar. The crushed bones are then chopped and incubated for 1 h at 37 degrees C in 20 ml of DMEM containing 0.2% (wt/vol) collagenase. The cell suspension is filtered before red blood cell lysis and incubated with the following antibodies: allophycocyanin (APC)-conjugated PDGFR-alpha, FITC-conjugated Sca-1, phycoerythrin (PE)-conjugated CD45 and Ter119. Appropriate gates are constructed on a cell sorter to exclude dead cells and lineage (CD45(+)Ter-119(+))-positive cells. Approximately 10,000 PalphaS MSCs may then be isolated per mouse. The total protocol takes ~7 h to complete.

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Antibacterial activity of povidone-iodine against an artificial biofilm of Porphyromonas gingivalis and Fusobacterium nucleatum

Hosaka, Y., Saito, A., Maeda, R., Fukaya, C., Morikawa, S., Makino, A., Ishihara, K. and Nakagawa, T.

Arch Oral Biol 57 （ 4 ） 364 - 8 2012年04月

ISSN 1879-1506

OBJECTIVE: To investigate the antibacterial activity of povidone-iodine (PVP-I) on an artificial dual species biofilm of periodontal pathogens. DESIGN: Porphyromonas gingivalis or Fusobacterium nucleatum grown in broth culture was inoculated on polycarbonate membrane (PCM) tissue culture inserts. After incubation for 72 h, PVP-I solutions were applied to the biofilm for the time period ranging from 0.5 to 5 min. After addition of a deactivator, each PCM was removed and the biofilm on the PCM was serially diluted and plated on blood agar plates and cultured anaerobically for 7 days. Then viable bacteria were enumerated. RESULTS: In the dual species biofilm model, F. nucleatum showed an approximately 200-fold increase in viable counts when compared with mono-microbial biofilm. In dual species biofilm, PVP-I with concentration equal to or greater than 2% was required to significantly reduce P. gingivalis and F. nucleatum. When the contact time of PVP-I was increased to 1 min or greater, no difference in antibacterial activity of PVP-I was observed in any concentration. CONCLUSION: These results suggest that 30s application of 2% PVP-I would be effective in suppressing both P. gingivalis and F. nucleatum in dual-species biofilm, and this provides clinical implication for the control of subgingival biofilm.

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Purified mesenchymal stem cells are an efficient source for iPS cell induction

Niibe, K., Kawamura, Y., Araki, D., Morikawa, S., Miura, K., Suzuki, S., Shimmura, S., Sunabori, T., Mabuchi, Y., Nagai, Y., Nakagawa, T., Okano, H. and Matsuzaki, Y.

PLoS One 6 （ 3 ） e17610 2011年03月

ISSN 1932-6203

BACKGROUND: Induced pluripotent stem (iPS) cells are generated from mouse and human somatic cells by the forced expression of defined transcription factors. Although most somatic cells are capable of acquiring pluripotency with minimal gene transduction, the poor efficiency of cell reprogramming and the uneven quality of iPS cells are still important problems. In particular, the choice of cell type most suitable for inducing high-quality iPS cells remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here, we generated iPS cells from PDGFRalpha+ Sca-1+ (PalphaS) adult mouse mesenchymal stem cells (MSCs) and PDGFRalpha(-) Sca-1(-) osteo-progenitors (OP cells), and compared the induction efficiency and quality of individual iPS clones. MSCs had a higher reprogramming efficiency compared with OP cells and Tail Tip Fibroblasts (TTFs). The iPS cells induced from MSCs by Oct3/4, Sox2, and Klf4 appeared to be the closest equivalent to ES cells by DNA microarray gene profile and germline-transmission efficiency. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that a purified source of undifferentiated cells from adult tissue can produce high-quality iPS cells. In this context, prospectively enriched MSCs are a promising candidate for the efficient generation of high-quality iPS cells.

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Mesp1+ early paraxial mesodermal cells supply initial bone marrow mesenchymal stem cells capable of differentiating into neural crest lineage cells

Niibe, K., Morikawa, S., Mabuchi, Y., Araki, D., Nakagawa, T., Okano, H. and Matsuzaki, Y.

Inflammation and Regeneration 31 （ 1 ） 116 - 124 2011年01月

ISSN 1880-9693

初期中胚葉特異的Mesp1-Cre/Floxed-EGFPをコードする成体トランスジェニックマウスの骨髄中に、沿軸中胚葉由来の間葉系幹細胞(MSC)を同定した。少量ではあるが有意な量のMesp1+細胞が成体骨髄に存在していた。骨髄中に検出されるEGFP+細胞の大部分は造血細胞画分に存在し、EGFP+MSCは骨細胞、脂肪細胞、軟骨細胞、神経細胞、グリア細胞および筋線維芽細胞に分化した。Mesp1-Cre/Floxed-EGFPマウス由来EGFP+MSCとEGFP-MSCとの間でin vitro特性の差はみられなかった。以上より、成体骨髄のMSCは複数の発生学的起源を持ち、MSCの一部はMesp1+初期沿軸中胚葉に由来すると考えられた。

Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation

Mukaino, M., Nakamura, M., Yamada, O., Okada, S., Morikawa, S., Renault-Mihara, F., Iwanami, A., Ikegami, T., Ohsugi, Y., Tsuji, O., Katoh, H., Matsuzaki, Y., Toyama, Y., Liu, M. and Okano, H.

Exp Neurol 224 （ 2 ） 403 - 14 2010年08月

ISSN 1090-2430

We previously reported the beneficial effect of administering an anti-mouse IL-6 receptor antibody (MR16-1) immediately after spinal cord injury (SCI). The purpose of our present study was to clarify the mechanism underlying how MR16-1 improves motor function after SCI. Quantitative analyses of inflammatory cells using flow cytometry, and immunohistochemistry with bone marrow-chimeric mice generated by transplanting genetically marked purified hematopoietic stem cells, revealed that MR16-1 dramatically switched the central player in the post-traumatic inflammation, from hematogenous macrophages to resident microglia. This change was accompanied by alterations in the expression of relevant cytokines within the injured spinal cord; the expression of recruiting chemokines including CCL2, CCL5, and CXCL10 was decreased, while that of Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), a known mitogen for microglia, was increased. We also showed that the resident microglia expressed higher levels of phagocytic markers than the hematogenous macrophages. Consistent with these findings, we observed significantly decreased tissue damage and reduced levels of myelin debris and Nogo-A, the axonal growth inhibitor, by MR16-1 treatment. Moreover, we observed increased axonal regeneration and/or sprouting in the MR16-1-treated mice. Our findings indicate that the functional improvement elicited by MR16-1 involves microglial functions, and provide new insights into the role of IL-6 signaling in the pathology of SCI.

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Inhibition of Abcg2 transporter on primitive hematopoietic stem cells by All-trans retinoic acid increases sensitivity to anthracycline

Lein, L., Nagai, Y., Mabuchi, Y., Suzuki, S., Morikawa, S. and Matsuzaki, Y.

Inflammation and Regeneration 30 （ 1 ） 55 - 62 2010年01月

ISSN 1880-9693

オールトランスレチノイン酸(RA)が乳癌耐性蛋白質(Abcg2)を阻害することを発見した。トランスポーター阻害薬レセルピンと同様に、RAは新たな転写の必要なく、造血幹細胞(HSC)のAbcg2を阻害することによりHoechst色素排出を用量依存的に抑制した。side population細胞に対するRAとレセルピンの作用は可逆的であり、wash-outにより消失した。Abcg2を安定発現するNIH3T3-GFP細胞でも同様の結果が得られた。RA処理HSCおよびAbcg2欠損HSCはドキソルビシンに高い感受性を示した。以上より、HSCの生存、増殖および分化以外に、RAはAbcg2トランスポーター阻害物質として機能すると考えられた。

Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow

Morikawa, S., Mabuchi, Y., Kubota, Y., Nagai, Y., Niibe, K., Hiratsu, E., Suzuki, S., Miyauchi-Hara, C., Nagoshi, N., Sunabori, T., Shimmura, S., Miyawaki, A., Nakagawa, T., Suda, T., Okano, H. and Matsuzaki, Y.

J Exp Med 206 （ 11 ） 2483 - 96 2009年10月

ISSN 1540-9538

Mesenchymal stem cells (MSCs) are defined as cells that undergo sustained in vitro growth and can give rise to multiple mesenchymal lineages. Because MSCs have only been isolated from tissue in culture, the equivalent cells have not been identified in vivo and little is known about their physiological roles or even their exact tissue location. In this study, we used phenotypic, morphological, and functional criteria to identify and prospectively isolate a subset of MSCs (PDGFRalpha+Sca-1+CD45-TER119-) from adult mouse bone marrow. Individual MSCs generated colonies at a high frequency and could differentiate into hematopoietic niche cells, osteoblasts, and adipocytes after in vivo transplantation. Naive MSCs resided in the perivascular region in a quiescent state. This study provides the useful method needed to identify MSCs as defined in vivo entities.

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Development of mesenchymal stem cells partially originate from the neural crest

Morikawa, S., Mabuchi, Y., Niibe, K., Suzuki, S., Nagoshi, N., Sunabori, T., Shimmura, S., Nagai, Y., Nakagawa, T., Okano, H. and Matsuzaki, Y.

Biochem Biophys Res Commun 379 （ 4 ） 1114 - 9 2009年02月

ISSN 1090-2104

Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells isolated from many adult tissues. Previous studies reported that MSCs can differentiate to both mesodermal and neural lineages by a phenomenon referred to as ''dedifferentiation'' or ''transdifferentiation''. However, since MSCs have only been defined in vitro, much of their development in vivo is still unknown. Here, we prospectively identified MSCs in the bone marrow from adult transgenic mice encoding neural crest-specific P0-Cre/Floxed-EGFP and Wnt1-Cre/Floxed-EGFP. EGFP-positive MSCs formed spheres that expressed neural crest stem cell genes and differentiated into neurons, glial cells, and myofibroblasts. Interestingly, we observed MSCs both in the GFP(+) and GFP(-) fraction and found that there were no significant differences in the in vitro characteristics between these two populations. Our results suggest that MSCs in adult bone marrow have at least two developmental origins, one of which is the neural crest.

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Prospective isolation and identification of human mesenchymal stem cells by flow cytometry

Mabuchi, Y., Morikawa, S., Suzuki, S., Sunabori, T., Okano, H. and Matsuzaki, Y.

Inflammation and Regeneration 29 （ 1 ） 73 - 78 2009年01月

ISSN 1880-9693

新鮮骨髄(BM)細胞のCD271発現パターンを調べ、線維芽細胞コロニー形成単位(CFU-F)を分析し、CD271が、標記分離・同定のマーカーにもなるか否か検討した。共発現分析の結果、CD271細胞はCD133にも陽性を示した。CD271+CD133+サブセットを分離後、CD271+CD133+画分において殆ど独占的にコロニー形成能が存在することが示された。BMから直接分離されたCD271+CD133+は高度に濃縮されたCFU-Fの個体群で、14日間培養後未分画細胞の720倍のコロニー数を示した。これら細胞は、脂質、骨細胞へと分化し、多系統分化能が示唆された。以上より、CD271とCD133は、標記分離に有用であることが示された。本細胞は脊髄損傷、軟骨修復、心筋梗塞等の疾患における移植のために使用し得ると考えられた。

Hzf regulates adipogenesis through translational control of C/EBPalpha

Kawagishi, H., Wakoh, T., Uno, H., Maruyama, M., Moriya, A., Morikawa, S., Okano, H., Sherr, C. J., Takagi, M. and Sugimoto, M.

EMBO J 27 （ 10 ） 1481 - 90 2008年05月

ISSN 1460-2075

Adipocyte differentiation requires a well-defined programme of gene expression in which the transcription factor C/EBPalpha (CCAAT/enhancer-binding protein) has a central function. Here, we show that Hzf (haematopoietic zinc-finger), a previously identified p53 transcriptional target, regulates C/EBPalpha expression. Hzf is induced during differentiation of preadipocyte cell lines, and its suppression by short hairpin RNA disrupts adipogenesis. In Hzf's absence, expression of C/EBPalpha is severely impaired because of reduced translation of its mRNA. Hzf physically interacts with the 3' untranslated region of C/EBPalpha mRNA to enhance its translation. Taken together, these findings underscore a critical role of Hzf in the adipogenesis regulatory cascade.

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Ontogeny and multipotency of neural crest-derived stem cells in mouse bone marrow, dorsal root ganglia, and whisker pad

Nagoshi, N., Shibata, S., Kubota, Y., Nakamura, M., Nagai, Y., Satoh, E., Morikawa, S., Okada, Y., Mabuchi, Y., Katoh, H., Okada, S., Fukuda, K., Suda, T., Matsuzaki, Y., Toyama, Y. and Okano, H.

Cell Stem Cell 2 （ 4 ） 392 - 403 2008年04月

ISSN 1875-9777

Although recent reports have described multipotent, self-renewing, neural crest-derived stem cells (NCSCs), the NCSCs in various adult rodent tissues have not been well characterized or compared. Here we identified NCSCs in the bone marrow (BM), dorsal root ganglia, and whisker pad and prospectively isolated them from adult transgenic mice encoding neural crest-specific P0-Cre/Floxed-EGFP and Wnt1-Cre/Floxed-EGFP. Cultured EGFP-positive cells formed neurosphere-like structures that expressed NCSC genes and could differentiate into neurons, glial cells, and myofibroblasts, but the frequency of the cell types was tissue source dependent. Interestingly, we observed NCSCs in the aorta-gonad-mesonephros region, circulating blood, and liver at the embryonic stage, suggesting that NCSCs migrate through the bloodstream to the BM and providing an explanation for how neural cells are generated from the BM. The identification of NCSCs in accessible adult tissue provides a new potential source for autologous cell therapy after nerve injury or disease.

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Two distinct stem cell lineages in murine bone marrow

Koide, Y., Morikawa, S., Mabuchi, Y., Muguruma, Y., Hiratsu, E., Hasegawa, K., Kobayashi, M., Ando, K., Kinjo, K., Okano, H. and Matsuzaki, Y.

Stem Cells 25 （ 5 ） 1213 - 21 2007年05月

ISSN 1066-5099

Mesenchymal stem cells (MSC), a distinct type of adult stem cell, are easy to isolate, culture, and manipulate in ex vivo culture. These cells have great plasticity and potential for therapeutic application, but their properties are poorly understood because of their low frequency and the lack of knowledge on cell surface markers and their location of origin. The present study was designed to address the undefined lineage relationship of hematopoietic and mesenchymal stem cells. Genetically marked, highly purified hematopoietic stem cells (HSCs) were transplanted into wild-type animals and, after bone marrow repopulation, the progeny were rigorously investigated for differentiation potential into mesenchymal tissues by analyzing in vitro differentiation into mesenchymal tissues. None/very little of the hematopoietic cells contributed to colony-forming units fibroblast activity and mesenchymal cell differentiation; however, unfractionated bone marrow cells resulted in extensive replacement of not only hematopoietic cells but also mesenchymal cells, including MSCs. As a result, we concluded that purified HSCs have no significant potency to differentiate into mesenchymal lineage. The data strongly suggest that hematopoietic cells and mesenchymal lineage cells are derived from individual lineage-specific stem cells. In addition, we succeeded in visualizing mesenchymal lineage cells using in vivo microimaging and immunohistochemistry. Flow cytometric analysis revealed CD140b (PDGFRbeta) could be a specific marker for mesenchymal lineage cells. The results may reinforce the urgent need for a more comprehensive view of the mesenchymal stem cell identity and characteristics. Disclosure of potential conflicts of interest is found at the end of this article.

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幹細胞を用いた新規口腔組織再生療法の確立

森川暁

Journal of Bio-Integration 5 （ 1 ） 9 - 12 2015年08月

ISSN 2186-2923

糖尿病患者における歯周病原細菌の血清抗体価に関する調査

太田淳也, 深谷千絵, 笠井俊輔, 赤松真也子, 森川暁, 田子森順子, 江口徹, 税所芳史, 河合俊英, 伊藤裕 and 中川種昭

日本歯周病学会会誌 56 （ 4 ） 414 - 422 2014年12月

ISSN 0385-0110

本研究は、糖尿病患者の歯周病のスクリーニングテストとしての、歯周病原細菌に対する血清IgG抗体価(以下抗体価)の有用性を検索するために行った。被験者は、2010年7月から2011年12月までに慶應義塾大学病院内科に教育入院した2型糖尿病患者28名(平均年齢56.6±10.7歳、男性18名、女性10名、平均罹患期間8.7±6.3年)(平均±標準偏差)とした。初診時に歯周組織検査と血液検査を施行後、歯周基本治療を行い、基本治療終了1ヵ月後に再評価を行った。抗体価検査はPorphyromonas gingivalis(Pg)、Prevotella intermedia(Pi)、Eikenella corrodens(Ec)、Aggregatibacter actinomycetemcomitans(Aa)の4菌種に行った。今回検索した検査値の中では、Pg抗体価と歯周病の病態に関連が認められ、抗体価1.0を境界値とした場合に低抗体価群と高抗体価群では、歯周ポケット深さにおいて有意差を認めた。また初診時のPg抗体価と歯周ポケット深さにおいて、有意に高い相関関係を示した。基本治療後の抗体価は低下傾向にあるものの、初診時との有意差は認めなかった。以上の結果から、糖尿病患者の歯周病スクリーニングにPgに対する血清抗体価が有用であり、その境界値は1.0付近にあることが示唆された。(著者抄録)

顎下部に生じた孤立性線維性腫瘍の1例

杉山健太郎, 森川暁, 山田学, 岩渕絵美, 岩渕博史 and 内山公男

日本口腔外科学会雑誌 59 （ 10 ） 632 - 636 2013年10月

ISSN 0021-5163

症例は23歳女性で、右側顎下部の腫脹を主訴とした。同部に30×20mm大の限局性、可動性、弾性軟の無痛性腫瘤を認め、熱感や発赤はなかった。MRIで腫瘤はT1強調画像で不均一な低信号、T2強調画像で中〜高信号を示し、大部分でガドリニウム造影効果を認め、腫瘤の下方に正常な顎下腺が圧排されていた。顎下腺良性腫瘍と診断し、手術を行い顎下腺を含め一塊として切除した。術後2年10ヵ月経過し、再発や転移はない。病理組織所見で、病変は境界明瞭な腫瘤で、周囲に線維性の被膜様構造が認められた。腫瘍は紡錘形〜短紡錘形細胞の密な増殖から成り、細胞異型は軽度で、核分裂像は少なかった。腫瘍内には大小不整形の血管腔が相当数介在し、血管周皮腫様の鹿の角様に分岐した血管も認めた。切除標本の割面に散在していた小腔に相当する部分には、裏装上皮や血管内皮細胞は認めなかった。免疫染色ではCD34およびbcl-2が陽性で、孤立性線維性腫瘍と病理診断した。

糖尿病患者における歯周病罹患状態と糖尿病合併症との関係

太田淳也, 深谷千絵, 笠井俊輔, 赤松真也子, 森川暁, 田子森順子, 江口徹, 税所芳史, 河合俊英, 伊藤裕 and 中川種昭

日本歯周病学会会誌 54 （ 4 ） 336 - 345 2012年12月

ISSN 0385-0110

本研究は糖尿病患者の歯周病罹患状況、ならびにその他の合併症との相互関係を明らかにすることを目的に行われた。被験者は、2010年7月から2011年12月までに内科に教育入院した2型糖尿病患者105名(平均年齢55.4±11.3歳)とした。評価項目として、現在歯数、プロービングポケットの深さ(PPD)、プロービング時の出血(BOP)、動揺度を測定した。また、背景因子として年齢・性別・体格指標(BMI)・糖尿病罹患期間・血圧・既往歴、糖尿病合併症に関する評価として網膜症の有無(SDR:単純性網膜症・PPDR:前増殖性網膜症・PDR:増殖性網膜症)、腎症の有無、神経障害の有無、動脈硬化性疾患の有無、血液指標を評価し比較検討した。今回の結果から糖尿病合併症である網膜症患者での残存歯数はPDR患者で他のステージの網膜症患者に比べ有意に少なく(p<0.01 vs SDR、p<0.05 vs PPDR)、4〜6mmPPD率や7mm以上PPD率ではSDR<PPDR<PDRとPPDが深い部位の割合が高くなる傾向を示しているため、網膜症の進行が歯周病の病態悪化になんらかの関与をしている可能性が考えられる。重度の歯周病(最大ポケット深さ7mm以上)を有する患者の割合は腎症以外で有意に高く、糖尿病合併症の有無と歯周病の進行度には相関があることが示された。(著者抄録)

当科における埋伏智歯のX線写真による検討

渡辺武夫, 山田有佳, 森川暁, 山田学, 小林大輔, 岩渕絵美, 岩渕博史 and 内山公男

栃木県歯科医学会誌 62 97 - 103 2010年04月

埋伏智歯抜歯の難易度を安全性という観点から簡便に判断できる指標を探索するため、当科で2006〜2008年にパノラマX線撮影された埋伏智歯3789本の写真をもとに、埋伏状態と下歯槽管や上顎洞との位置関係について検討した。その結果、[埋伏の深さ]や[歯軸方向][萠出スペース]は上顎においてはあまり適切な指標とはいえないが、下顎においては抜歯のリスクを簡便に判断できる指標になると考えられた。

知覚神経異常を伴った上下顎大量骨融解症の1例

若林類, 矢郷香, 森川暁, 中川種昭, 朝波惣一郎 and 向井萬起男

日本口腔外科学会雑誌 54 （ 9 ） 550 - 554 2008年09月

ISSN 0021-5163

25歳女。左側下顎臼歯部歯肉腫脹および疼痛、左側オトガイ神経麻痺、右側上顎歯肉の腫脹で受診した。セフトリアキソンナトリウムの静脈内投与を開始した。激痛を伴っていたため、疼痛コントロール目的で入院した。ジクロフェナクナトリウムが無効であったが、硫酸モルヒネで良好な疼痛コントロールが得られた。生検による病理組織学的診断では炎症性病変もしくは形質細胞腫を疑った。抗菌薬は無効で、上下顎とも骨融解が急速に進行した。確定診断が得られなかったが、骨髄炎様病態を呈する顎骨腫瘍の診断で、全身麻酔下、上顎骨部分切除術、下顎骨区域切除術、再建用チタンプレートによる再建術を施行した。術後再発もなく、下顎欠損部に腸骨移植を施行した。術後約3年の現在、骨融解も停止し、自発痛もなく経過は良好である。病理組織学的に上下顎大量骨融解症と診断した。

先天性ガマ腫の1例

森川暁, 矢郷香, 岡田明子, 中川種昭, 朝波惣一郎 and 田中陽一

日本口腔外科学会雑誌 51 （ 12 ） 618 - 621 2005年12月

ISSN 0021-5163

生後4ヵ月の男児.患者は出生時より口底部の腫脹を認め,精査目的で著者らの施設へ紹介となった.初診時,口底右側部から正中を越える表面平滑な半球状の腫脹を認め,MRIでは口底正中部に約30×25mm大の境界明瞭なT1にて低信号,T2にて高信号の病変が顎舌骨筋の上方に認められた.以上より,先天性ガマ腫(舌下型)と診断のもと,生後7ヵ月時に開窓術を施行した.病理組織学的に粘液貯留嚢胞と診断され,術後1年3ヵ月経過現在,再発なく経過良好である

術前検査が契機となり自己免疫性肝炎に罹患した1例

矢郷香, 森川暁, 山田学, 岡田豊, 中川種昭 and 朝波惣一郎

有病者歯科医療 14 （ 2 ） 95 - 99 2005年09月

ISSN 0918-8150

18歳女.歯列不正で受診した.パノラマX線写真で右側下顎智歯部にX線透過像を指摘され受診した.下顎骨嚢胞の臨床診断で,全身麻酔下嚢胞摘出術を予定した.術前検査でASTとALTが高値であった.肝生検を施行した.自己免疫性肝炎と診断し,プレドニゾロンを開始した.手術を延期していたが,右側頬部腫脹および右側下顎智歯部より排膿を認め,下顎骨嚢胞摘出術および智歯の抜歯術を施行した.病理診断は歯原性角化嚢胞であった.現在,術後約1年10ヵ月経過するも下顎骨嚢胞の再発はなく経過良好である

フラップ手術を始める前に知っておくこと　6 全身状態を知ろう

中川種昭, 二階堂雅彦, 北島一, 長谷川嘉明, 吉野敏明, 高橋潤一, 藤本浩平, 片山明彦, 吉野宏幸, 斉田寛之, 田中真喜, 森川暁, 井原雄一郎, 中山亮平, 巻島由香里, 髙橋優子, 井上孝 and 石原和幸

フラップ手術のすすめ　基本手技＋歯周組織再生療法・歯周形成外科（医歯薬出版株式会社） 39 - 45 2018年06月

幸齢化を支える医学　命を狙う?!　歯周病の話

森川暁

交詢雑誌 626 43 - 61 2017年07月

口腔領域における再生医療の最前線①　口腔上皮の再生

森川暁, 黄地健仁, 中川種昭, 河奈裕正 and 岡野栄之

the Quintessence 口腔外科 YEAR BOOK 一般臨床家，口腔外科医のための口腔外科ハンドマニュアル'15 156 - 160 2015年08月

歯周組織の再生を目指した間葉系幹細胞の研究

中川種昭 and 森川暁

歯科学報 112 （ 5 ） 624 - 630 2012年10月

ISSN 0037-3710

【再生医療へ進む最先端の幹細胞研究　注目のiPS・ES・間葉系幹細胞などの分化・誘導の基礎と、各種疾患への臨床応用】幹細胞の基礎医学　間葉系幹細胞の同定とその分離法

馬渕洋, 森川暁, 砂堀毅彦 and 松崎有未

実験医学 26 （ 5 ） 68 - 73 (676-681) 2008年03月

ISSN 0288-5514

骨髄には多能性をもつ間葉系幹細胞が存在し、血球系細胞の増殖・分化を調節する一方で、成体間葉系組織の修復・恒常性の維持に寄与していると考えられている。しかしながら、間葉系幹細胞は現状においてin vitroにて定義されている幹細胞であり、このことが生体内での分布や、骨髄中での生理的機能の解析を困難にしている。そこで、フローサイトメトリーを用いて、予期的に間葉系幹細胞を同定・分離し、その性状を解析する試みが行われている。この方法を用いることで、性質変化や他細胞の影響のない均一な間葉系幹細胞を得ることが可能となり、これまで明らかにされてこなかった真の分化能、生体内における局在、あるいはその生理的機能を解明することができると考えられる。(著者抄録)

【組織幹細胞と多能性幹細胞　わが国における幹細胞研究の最前線】組織幹細胞　間葉系幹細胞の予期的な分離・同定

馬渕洋, 森川暁, 砂堀毅彦 and 松崎有未

再生医療 6 （ 3 ） 31 - 36 (263-268) 2007年08月

ISSN 1347-7919

幹細胞技術の現状と展望　成体に存在する多能性幹細胞

森川暁, 馬渕洋 and 松崎有未

蛋白質・核酸・酵素 52 （ 8 ） 906 - 912 2007年07月

ISSN 0039-9450

これまで再生医療については,皮膚移植や骨髄移植のほか,パーキンソン病患者へのドーパミン産生細胞の移植などが行なわれてきた.しかし,移植組織が極端に不足しているという問題があり,その解決方策のひとつとして幹細胞を利用した細胞移植治療の確立が望まれている.本稿では,幹細胞の再生医学における供給源としての有用性に着目し,とくに体内から取り出しやすい幹細胞,すなわち,骨髄中に存在するとされている幹細胞に焦点をあてた.骨髄中の間葉系幹細胞に関する研究の進展について,骨髄中に存在する成体多能性幹細胞および中胚葉系幹細胞について,また,骨髄以外の組織に存在するとされている神経堤由来幹細胞について,それぞれの関係を中心にその関連性を考察する.(著者抄録)

Treatment of calcium channel blocker-induced gingival overgrowth without modifying medication

Morikawa S., Nasu M., Miyashita Y., Nakagawa T.

Drug and therapeutics bulletin （Drug and therapeutics bulletin） 60 （ 3 ） 44 - 47 2022年03月

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Proposed protocol for treatment of severe periodontitis without platelet transfusion in patients with aplastic anemia: a case report

Morikawa S., Watanabe K., Usuda S., Miyashita Y., Nakagawa T.

Journal of Medical Case Reports （Journal of Medical Case Reports） 15 （ 1 ） 2021年12月

Background: Aplastic anemia is an intractable disease characterized by pancytopenia, susceptibility to infection, and difficulty in achieving hemostasis. In patients with severe periodontal disease and aplastic anemia, spontaneous bleeding from the gingival tissue due to thrombocytopenia and during brushing is common, which may further exacerbate dental issues. Comprehensive periodontal treatment for patients with aplastic anemia is highly challenging and requires collaboration with a hematologist. Here, we discuss the case of a patient with aplastic anemia and severe periodontitis who was successfully treated in collaboration with our hematology department. Case presentation: A 36-year-old Japanese woman with chief complaints of spontaneous gingival bleeding, pain, and increasing tooth mobility consulted our department. She had developed pancytopenia at age 11 years and was later diagnosed with aplastic anemia, making her susceptible to infection due to leukopenia. The results of the initial periodontal examination led to a diagnosis of severe generalized periodontitis (generalized stage IV grade C periodontitis) caused by leukopenia and poor oral hygiene. We adopted a comprehensive treatment plan, including invasive dental procedures. The patient exhibited no postoperative bleeding due to aplastic anemia-induced thrombocytopenia and experienced a good outcome. Conclusions: Both physicians and dentists should be aware that immunocompromised patients with aplastic anemia are at risk of developing severe periodontitis with severe alveolar bone resorption if the condition is combined with poor oral hygiene. Even in the presence of aplastic anemia, patients with severe periodontitis can undergo comprehensive dental treatment, including dental extraction and periodontal surgery, if bleeding and susceptibility to infection are controlled. This requires the cooperation of the patient and hematologists and can ultimately contribute to improving the patient’s quality of life.

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Mscs become collagen-type i producing cells with different phenotype in allogeneic and syngeneic bone marrow transplantation

Rusch R.M., Ogawa Y., Sato S., Morikawa S., Inagaki E., Shimizu E., Tsubota K., Shimmura S.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 22 （ 9 ） 2021年05月

ISSN 16616596

Mesenchymal stem cells (MSCs) have been widely used in therapeutic applications for many decades. However, more and more evidence suggests that factors such as the site of origin and pre-implantation treatment have a crucial impact on the result. This study investigates the role of freshly isolated MSCs in the lacrimal gland after allogeneic transplantation. For this purpose, MSCs from transgenic GFP mice were isolated and transplanted into allogeneic and syngeneic recipients. While the syngeneic MSCs maintained a spherical shape, allogeneic MSCs engrafted into the tissue as spindle-shaped cells in the interstitial stroma. Furthermore, the MSCs produced collagen type I in more than 85% to 95% of the detected GFP+ MSCs in the recipients of both models, supposedly contributing to pathogenic fibrosis in allogeneic recipients compared to syngeneic models. These findings indicate that allogeneic MSCs act completely differently from syngeneic MSCs, highlighting the importance of understanding the exact mechanisms behind MSCs.

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Management of generalized severe periodontitis using full-mouth disinfection and systemic antibiotics in a leukemic patient before stem cell transplantation: A case report

Morikawa S., Tsunoda K., Miyashita Y., Nasu M., Horie N., Usuda S., Kato J., Mori T., Nakagawa T.

Clinical Case Reports （Clinical Case Reports） 9 （ 2 ） 644 - 649 2021年02月

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Treatment of calcium channel blocker-induced gingival overgrowth without modifying medication

Morikawa S., Nasu M., Miyashita Y., Nakagawa T.

BMJ Case Reports （BMJ Case Reports） 14 （ 1 ） 2021年01月

Gingival overgrowth is a common side effect of calcium channel blockers used in the treatment of cardiovascular diseases. While controversial, management includes discontinuing the calcium channel blocker. We report the case of a 66-year-old Japanese man with hypertension and type 2 diabetes mellitus who was diagnosed with severe periodontitis covering almost all the teeth. The patient had been on nifedipine (40 mg/day) and amlodipine (10 mg/day) medication for 5 years. With his physician's consent, nifedipine was discontinued during his treatment for periodontitis, which consisted of oral hygiene instructions and scaling and root planing on all areas. Gingivectomy was performed on the areas of hard fibrous swelling. Nifedipine was resumed during periodontal treatment when the patient's hypertension worsened. His periodontal scores improved when he resumed treatment. We report that significant improvement in gingival overgrowth can occur with basic periodontal treatment, surgery and sustained intensive follow-up without adjusting calcium channel blockers.

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RT-PCR screening tests for SARS-CoV-2 with saliva samples in asymptomatic people: Strategy to maintain social and economic activities while reducing the risk of spreading the virus

Oba J., Taniguchi H., Sato M., Takamatsu R., Morikawa S., Nakagawa T., Takaishi H., Saya H., Matsuo K., Nishihara H.

Keio Journal of Medicine （Keio Journal of Medicine） 70 （ 2 ） 35 - 43 2021年

ISSN 00229717

The year 2020 will be remembered for the coronavirus disease 2019 (COVID-19) pandemic, which continues to affect the whole world. Early and accurate identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fundamental to combat the disease. Among the current diagnostic tests, real-time reverse transcriptase–polymerase chain reaction (RT-qPCR) is the most reliable and frequently used method. Herein, we discuss the interpretation of RT-qPCR results relative to viral infectivity. Although nasopharyngeal swab samples are often used for RT-qPCR testing, they require collection by trained medical staff. Saliva samples are emerging as an inexpensive and efficient alternative for large-scale screening. Pooled-sample testing of saliva has been applied for mass screening of SARS-CoV-2 infection. Current policies recommend isolating people with borderline cycle threshold (Ct) values (35<Ct <40), despite these Ct values indicating minimal infection risk. We propose the new concept of a “social cut-off” Ct value and risk stratification based on the correlation of Ct with infectivity. We also describe the experience of RT-qPCR screening of saliva samples at our institution. It is important to implement a scientific approach to minimize viral transmission while allowing economic and social activities to continue.

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Vertical Displacement in Unilateral Extension Base Flexible Removable Dentures

Horie N., Ouchi T., Nishiyama R., Usuda S., Morikawa S., Asoda S., Nakagawa T.

The Bulletin of Tokyo Dental College （The Bulletin of Tokyo Dental College） 60 （ 4 ） 233 - 239 2019年12月

ISSN 00408891

The need for flexible thermoplastic denture base materials has increased due to patient demand for better esthetic outcomes. Designs aimed at improving esthetic outcomes can cause difficulties for prosthodontists, however, from the viewpoint of function and maintenance. Therefore, the purpose of this study was to investigate vertical displacement in unilateral extension base denture models, comparing that obtained by flexible removable dentures with that by conventional metal clasp dentures. Models of unilateral extension base flexible removable dentures for mandibular defects were prepared. Periodontal ligament and jaw mucosa were simulated using a silicone impression material. Four types of flexible removable denture, with or without a metal rest, and two metal clasp dentures made of acrylic resin as a conventional design were used as dental prostheses. The amount of vertical displacement in the defect areas was measured under a load of 50 N at the first and second molars. Among the 6 types of dentures investigated, the amount of vertical displacement was greater with flexible removable dentures than with metal clasp dentures. This vertical displacement tended to decrease significantly, however, with the use of a metal rest with the flexible removable dentures. Esteshot with a metal rest, in particular, showed the smallest amount of displacement in the flexible removable dentures (first molar, 0.265±0.007 mm; second molar, 0.423±0.008 mm). These results indicate the importance of the application of rests in unilateral extension base flexible removable dentures. It may be useful to employ a metal rest in conjunction with a flexible removable denture to reduce load on the underlying mucosa, as is done with conventional partial dentures.

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