Viral delivery of L1CAM promotes axonal extensions by embryonic cerebral grafts in mouse brain

遺伝子治療によるホスト脳の環境最適化が細胞移植効果を高める --ホスト脳へのL1CAMの強制発現によるマウス胎仔脳移植片の軸索伸長促進効果--. 京都大学プレスリリース. 2023-03-24.Combining cell transplantation and gene therapy to enhance axonal outgrowth in the central nervous system. 京都大学プレスリリース. 2023-04-06.Cell replacement therapy is expected as a new and more radical treatment against brain damage. We previously reported that transplanted human cerebral organoids extend their axons along the corticospinal tract in rodent brains. The axons reached the spinal cord but were still sparse. Therefore, this study optimized the host brain environment by the adeno-associated virus (AAV)-mediated expression of axon guidance proteins in mouse brain. Among netrin-1, SEMA3, and L1CAM, only L1CAM significantly promoted the axonal extension of mouse embryonic brain tissue-derived grafts. L1CAM was also expressed by donor neurons, and this promotion was exerted in a haptotactic manner by their homophilic binding. Primary cortical neurons cocultured on L1CAM-expressing HEK-293 cells supported this mechanism. These results suggest that optimizing the host environment by the AAV-mediated expression of axon guidance molecules enhances the effect of cell replacement therapy

Isolation of Human Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation

Daisuke Doi, Bumpei Samata, Mitsuko Katsukawa, Tetsuhiro Kikuchi, Asuka Morizane, Yuichi Ono, Kiyotoshi Sekiguchi, Masato Nakagawa, Malin Parmar, and Jun Takahashi, "Isolation of Human Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation", Stem Cell Reports, 2, 3, 337-350, Cell Press, 201

Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1

Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1 + cells survive and differentiate into mDA neurons in vivo, resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1 + cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients

Unruptured medial paraclinoid internal carotid artery aneurysm embedded within symptomatic nonfunctioning pituitary giant adenoma: A high-risk comorbid pathology in transsphenoidal surgery and its countermeasures

Background: Injury of the internal carotid artery (ICA) in the cavernous portion is one of the most critical complications of transsphenoidal surgery (TSS), especially in cases of coexistence with a pituitary adenoma (PA) and ICA aneurysm. Case description: We present a rare case of unruptured medial paraclinoid ICA aneurysm (ICA-An) associated with symptomatic nonfunctioning giant PA. After endovascular coil embolization of the unruptured 4-mm saccular medial paraclinoid ICA-An, the patient underwent adenomectomy through an endoscopic endonasal TSS. During the bone resection over the right sellar floor near the right cavernous sinus, a tangle of packed coils in the treated medial paraclinoid ICA-An was observed immediately after a bite of a Kerrison rongeur. The dural layer over the coiled aneurysm had become thin to the point of transparency or complete absence. Careful inspection revealed that the bone hillock was formed by the medial paraclinoid ICA-An. Gross total resection of the adenoma was achieved without vascular injuries related to the coiled aneurysm despite postoperative transient right oculomotor paresis. Conclusions: This case conveys three important lessons about TSS: 1) coil embolization will manage a medial paraclinoid ICA-An as a sufficient preoperative procedure for TSS; 2) a medial paraclinoid ICA-An can appear directly under the sellar floor as an apparent extradural aneurysm; and; 3) surgeons should take great care in procedures near a coil-embolized medial paraclinoid ICA-An because the aneurysmal wall can be thin to the point of transparency. Keywords: Medial paraclinoid internal carotid artery aneurysm, Coil embolization, Extradural unruptured aneurysm, Pituitary giant adenoma, Endoscopic endonasal transsphenoidal surger