Publisher：株式会社医学書院  

DOI： 10.11477/mf.1411203266

Language：English   Publishing type：Research paper (scientific journal)  

Macrophages aid in wound healing by changing their phenotype and can be a key driver of fibrosis. However, the contribution of macrophage phenotype to fibrosis following vocal fold injury remains unclear. Peroxisome proliferator-activated receptor-γ (PPARγ) is expressed mainly by macrophages during early wound healing and regulates the macrophage phenotype. This study aimed to evaluate the effects of pioglitazone, a PPARγ agonist, on the macrophage phenotype and fibrosis following vocal fold injury in rats. Pioglitazone was injected into the rats' vocal folds on days 1, 3, 5, and 7 after injury, and the vocal fold lamina propria was evaluated on days 4 and 56 after injury. Moreover, THP-1-derived macrophages were treated with pioglitazone, and the expression of pro-inflammatory cytokines under lipopolysaccharide/interferon-γ stimulation was analyzed. The results revealed that pioglitazone reduced the expression of Ccl2 both in vivo and in vitro. Furthermore, pioglitazone decreased the density of inducible nitric oxide synthase+ CD68+ macrophages and inhibited the expression of fibrosis-related factors on day 4 after injury. On day 56 after injury, pioglitazone inhibited fibrosis, tissue contracture, and hyaluronic acid loss in a PPARγ-dependent manner. These results indicate that PPARγ activation could inhibit accumulation of inflammatory macrophages and improve tissue repair. Considered together, these findings imply that inflammatory macrophages play a key role in vocal fold fibrosis.

DOI： 10.1016/j.ajpath.2022.02.002

DOI： 10.1016/j.ajpath.2022.02.002

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

The nasal mucosa functions as a frontline biological defense against various foreign substances and pathogens. Maintaining homeostasis of the nasal epithelium is necessary to promote good health. Nasal epithelia are constantly replaced under normal conditions. However, hereditary diseases, including primary ciliary dyskinesia and cystic fibrosis, can result in intractable dysfunction of the nasal mucosa. Since there is no treatment for this underlying condition, extrinsic manipulation is necessary to recover and maintain nasal epithelia in cases of hereditary diseases. In this study, we explored the use of airway epithelial cells (AECs), including multi-ciliated airway cells (MCACs), derived from human induced pluripotent stem cells (hiPSCs) on porcine atelocollagen vitrigel membranes, as a candidate of a therapeutic method for irreversible nasal epithelial disorders. To confirm the regenerative capacity of iPSC-derived AECs, we transplanted them into nasal cavities of nude rats. Although the transplanted cells were found within cysts isolated from the recipient nasal respiratory epithelia, they survived in some rats. Furthermore, the surviving cells were composed of multiple cell types similar to the human airway epithelia. The results could contribute to the development of novel transplantation-related technologies for the treatment of severe irreversible nasal epithelial disorders.

DOI： 10.1089/ten.TEA.2021.0071

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1089/ten.TEA.2021.0071.

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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.

DOI： 10.1016/j.scr.2021.102233

DOI： 10.1016/j.scr.2021.102233

PubMed

Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

気管喉頭は硝子軟骨により枠組みを保持されており,呼吸,発声,嚥下機能を担う重要な臓器である.しかし,外傷や炎症性疾患・悪性腫瘍に対する手術などで軟骨が欠損した場合,枠組みが維持できなくなり,その機能は大きく損なわれる.硝子軟骨はそれ自体に再生能が乏しいため,気管喉頭軟骨欠損に対して,これまで組織工学を応用したさまざまな軟骨再生方法の開発,研究が行われてきた.足場としては非吸収性足場素材や脱細胞組織が臨床応用されたが,前者は枠組みの安定性は得られるものの,大きさが不変であるため小児への適応が困難であり,後者はドナーの確保や長期的な内腔保持困難が課題であった.一方,細胞移植(+足場素材)による軟骨組織再生では,軟骨細胞や間葉系幹細胞(MSC)を用いた移植法が,治験の段階ではあるが,一部で臨床応用されている.しかし,初代培養の軟骨細胞やMSCでは培養時に生じる細胞の脱分化や増殖能の低下が課題として残っている.また,近年,無限増殖能・多分化能を有するiPS細胞から軟骨細胞やMSCへの分化誘導法が開発され,特に膝関節領域においては臨床研究も実施されている.しかし,気管喉頭領域におけるiPS細胞由来細胞を用いた軟骨再生研究はいまだ少なく,確立された方法はない.今後,細胞移植が確立されるためには,必要な細胞を効率よく誘導したり,必要な数だけ確保したりする,細胞の動態をコントロールする技術が必要となる.医工学分野の新しい技術を適切に応用し,気管喉頭の安全かつ確実な軟骨再生方法が確立されることが期待される.(著者抄録)

Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

Language：Japanese