コラーゲンビトリゲル膜を用いたヒトiPS細胞由来気道上皮細胞のラット鼻腔への移植

京都大学新制・課程博士博士(医学)甲第24129号医博第4869号新制||医||1059(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 平井 豊博, 教授 中島 貴子, 教授 森本 尚樹学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

Neuroprotective role of insulin-like growth factor 1 in auditory and other nervous systems

Insulin-like growth factor 1 (IGF1) exerts an influence on almost every organ system in the body and plays an important role in growth, development, and metabolism. In the nervous system, IGF1 acts by promoting the development and growth of neurons and glial cells, differentiation of Schwann cells and their migration to axons, neurite outgrowth, and neuronal survival. The lack of IGF1 is associated with several pathological conditions, including severe prenatal growth retardation, postnatal growth failure, microcephaly, mental retardation, and bilateral sensorineural hearing loss. In addition to its physiological effects, based on the findings of in vivo and in vitro experiments and clinical trials, IGF1 is considered to play a potential role in the treatment of various types of neuronal damage. In this review, we discuss the potential use of IGF1 as a therapeutic molecule in the nervous system: (1) auditory system, including hair cells, cochlear ribbon synapses, auditory nerve, and central nervous systems, and (2) other peripheral nervous systems, especially the olfactory system and facial nerve. The role of IGF1 in the progression of age-related sensory deficits, especially hearing loss and olfactory dysfunction, is also discussed. Recent studies on IGF1 demonstrated that exogenous IGF1 can be applied in many fields, thus supporting the continued evaluation of IGF1 as a potential therapeutic molecule. Additional scientific investigations should be conducted to further supplement recent findings

Transplantation of a human induced pluripotent stem cell-derived airway epithelial cell sheet into the middle ear of rats

[Introduction] Early postoperative regeneration of the middle ear mucosa is essential for the prevention of postoperative refractory otitis media and recurrent cholesteatoma. As a means for intractable otitis media management, we focused on human induced pluripotent stem cell (hiPSC)-derived airway epithelial cells (AECs), which have been used in upper airway mucosal regeneration and transplantation therapy. In this study, we transplanted hiPSC-derived AECs into the middle ear of immunodeficient rats. [Methods] Following the preparation of AEC sheets from hiPSCs, the bilateral middle ear mucosa of X-linked severe combined immunodeficient rats was scraped, and the AEC sheets were transplanted in the ears unilaterally. [Results] Human nuclear antigen (HNA)-positive ciliated cells were observed on the transplanted side of the middle ear cavity surface in three of six rats in the 1-week postoperative group and in three of eight rats in the 2-week postoperative group. No HNA-positive cells were found on the control side. The percentage of HNA-positive ciliated cells in the transplanted areas increased in the 2-week postoperative group compared with the 1-week group, suggesting survival of hiPSC-derived AECs. Additionally, HNA-positive ciliated cells were mainly located at sites where the original ciliated cells were localized. Immunohistochemical analysis showed that the transplanted AECs contained cytokeratin 5- and mucin 5AC-positive cells, indicating that both basal cells and goblet cells had regenerated within the middle ear cavity. [Conclusions] The results of this study are an important first step in the establishment of a novel transplantation therapy for chronic otitis media

In vivo regeneration of rat laryngeal cartilage with mesenchymal stem cells derived from human induced pluripotent stem cells via neural crest cells

The laryngotracheal cartilage is a cardinal framework for the maintenance of the airway for breathing, which occasionally requires reconstruction. Because hyaline cartilage has a poor intrinsic regenerative ability, various regenerative approaches have been attempted to regenerate laryngotracheal cartilage. The use of autologous mesenchymal stem cells (MSCs) for cartilage regeneration has been widely investigated. However, long-term culture may limit proliferative capacity. Human-induced pluripotent stem cell-derived MSCs (iMSCs) can circumvent this problem due to their unlimited proliferative capacity. This study aimed to investigate the efficacy of iMSCs in the regeneration of thyroid cartilage in immunodeficient rats. Herein, we induced iMSCs through neural crest cell intermediates. For the relevance to prospective future clinical application, induction was conducted under xeno-free/serum-free conditions. Then, clumps fabricated from an iMSC/extracellular matrix complex (C-iMSC) were transplanted into thyroid cartilage defects in immunodeficient rats. Histological examinations revealed cartilage-like regenerated tissue and human nuclear antigen (HNA)-positive surviving transplanted cells in the regenerated lesion. HNA-positive cells co-expressed SOX9, and type II collagen was identified around HNA-positive cells. These results indicated that the transplanted C-iMSCs promoted thyroid cartilage regeneration and some of the iMSCs differentiated into chondrogenic lineage cells. Induced MSCs may be a promising candidate cell therapy for human laryngotracheal reconstruction

Laryngeal Cartilage Regeneration of Nude Rats by Transplantation of Mesenchymal Stem Cells Derived from Human-Induced Pluripotent Stem Cells

Previous studies transplanted human-induced pluripotent stem cells (hiPSCs)-derived mesenchymal stem cells (iMSCs) into thyroid cartilage defect of X-liked severe combined immunodeficiency (X-SCID) rats and confirmed transplanted cell survival and cartilage regeneration. Thus, this study aimed to investigate the contribution of iMSC transplantation to thyroid cartilage regeneration of nude rats. iMSCs were induced from hiPSCs via a neural crest cell lineage. Then, clumps formed from an iMSC/extracellular matrix complex were transplanted into thyroid cartilage defects in nude rats. The larynx was removed and histological and immunohistochemical analyses were performed 4 or 8 weeks after the transplantation. Human nuclear antigen (HNA)-positive cells were observed in 11 of 12 (91.7%) rats, which indicated that transplanted iMSCs survived in thyroid cartilage defects in nude rats. HNA-positive cells co-expressed SOX9, and type II collagen was identified around HNA-positive cells in 8 of 12 rats (66.7%), which indicated cartilage-like regeneration. Cartilage-like regeneration in nude rats in this study was comparable to the previous report on X-SCID rats (HNA-positive cells were observed in all 14 rats and cartilage-like regeneration was observed in 10 of 14 rats). This result suggests that nude rats could be an alternative to X-SCID rats in thyroid cartilage regeneration experiments using iMSCs, and this nude rat cartilage transplantation model may develop cartilage regeneration research concerning fewer problems such as infection due to immunosuppression

Neuroprotective role of insulin-like growth factor 1 in auditory and other nervous systems

y. Insulin-like growth factor 1 (IGF1) exerts an influence on almost every organ system in the body and plays an important role in growth, development, and metabolism. In the nervous system, IGF1 acts by promoting the development and growth of neurons and glial cells, differentiation of Schwann cells and their migration to axons, neurite outgrowth, and neuronal survival. The lack of IGF1 is associated with several pathological conditions, including severe prenatal growth retardation, postnatal growth failure, microcephaly, mental retardation, and bilateral sensorineural hearing loss. In addition to its physiological effects, based on the findings of in vivo and in vitro experiments and clinical trials, IGF1 is considered to play a potential role in the treatment of various types of neuronal damage. In this review, we discuss the potential use of IGF1 as a therapeutic molecule in the nervous system: (1) auditory system, including hair cells, cochlear ribbon synapses, auditory nerve, and central nervous systems, and (2) other peripheral nervous systems, especially the olfactory system and facial nerve. The role of IGF1 in the progression of age-related sensory deficits, especially hearing loss and olfactory dysfunction, is also discussed. Recent studies on IGF1 demonstrated that exogenous IGF1 can be applied in many fields, thus supporting the continued evaluation of IGF1 as a potential therapeutic molecule. Additional scientific investigations should be conducted to further supplement recent findings

Two cases with an interseptal sinus cell mucocele: The different mechanisms of the development varying in the time of the onset

Intersinus septal cells (ISSC) are defined as cells confined to the thin septum separating the frontal sinuses. In 2008, Som et al. first described four cases with a mucocele proved to have arisen in ISSC. Here, we report two cases with a mucocele in ISSC, representing the second report to appear in the English literature. Case 1 involved a mucocele in the center of the frontal lesion with rudimentary bilateral frontal sinuses, which suggested that the ISSC mucocele occurred during very early development of the frontal sinuses. Case 2 concerned a mucocele in the unilocular frontal sinus invading the left orbit. The frontal sinus septum was destroyed with partial ‘Y’-shaped remnants, which implied the ballooning and bursting of the ISSC mucocele into both sides of the frontal sinus. The two different mechanisms of development of the ISSC mucoceles may vary in relation to the time of onset

sj-docx-1-cll-10.1177_09636897241228026 – Supplemental material for Changes in the Proportion of Each Cell Type After hiPSC-Derived Airway Epithelia Transplantation

Supplemental material, sj-docx-1-cll-10.1177_09636897241228026 for Changes in the Proportion of Each Cell Type After hiPSC-Derived Airway Epithelia Transplantation by Masayuki Kitano, Yasuyuki Hayashi, Hiroe Ohnishi, Hideaki Okuyama, Masayoshi Yoshimatsu, Keisuke Mizuno, Fumihiko Kuwata, Takeshi Tada, Yo Kishimoto, Satoshi Morita and Koichi Omori in Cell Transplantation</p

sj-tiff-3-cll-10.1177_09636897241228026 – Supplemental material for Changes in the Proportion of Each Cell Type After hiPSC-Derived Airway Epithelia Transplantation

Supplemental material, sj-tiff-3-cll-10.1177_09636897241228026 for Changes in the Proportion of Each Cell Type After hiPSC-Derived Airway Epithelia Transplantation by Masayuki Kitano, Yasuyuki Hayashi, Hiroe Ohnishi, Hideaki Okuyama, Masayoshi Yoshimatsu, Keisuke Mizuno, Fumihiko Kuwata, Takeshi Tada, Yo Kishimoto, Satoshi Morita and Koichi Omori in Cell Transplantation</p