人間の皮膚のソマティックコピーナンバー・モザイシズムは,誘発された多能幹細胞によって明らかになりました
Alexej Abyzov1, Jessica Mariani, Dean Palejev
1Program in Neurodevelopment and Regeneration, Yale University, New Haven, Connecticut 06520, USA.
Nature
|November 20, 2012
まとめ
誘発性多能幹細胞 (iPSCs) の再プログラミングは,通常,新しいDNA複製数変異 (CNVs) を引き起こしません. iPSCsのほとんどのCNVは,親の皮膚細胞に既にある低周波の変種から発生し,広範囲にわたる体的モザイク主義を明らかにします.
科学分野:
- ゲノミクスゲノミクスとは
- 幹細胞生物学 幹細胞生物学
- エピジェネティクス エピジェネティクス
背景:
- 誘発性多能幹細胞 (iPSC) は,再生医療と疾患モデリングにおいて極めて重要です.
- 遺伝子改変,特に複製数変異 (CNVs) に関する懸念は,再プログラムプロセス中に発生します.
- iPSCsの遺伝的安定性を理解することは,それらの安全な臨床応用に不可欠です.
研究 の 目的:
- ソマティック細胞をiPSCに再プログラムすることで,新しいコピー数変異 (CNVs) が起こるかどうかを調査する.
- 人間のiPSC系で観察されたCNVの起源と頻度を特徴付けるため.
- 低頻度の体性ゲノム変異の検出のためのiPSCのクローン拡張の有用性を評価する.
主な方法:
- 20人のヒトのiPSC線およびその親の皮膚原生線維芽細胞の全ゲノムおよびトランスクリプトーム配列解析.
- 総合的なゲノム分析のための次世代シーケンシング (NGS).
- ポリメラーゼ連鎖反応 (PCR) とデジタルドロップレットPCRは,CNVの検証を目的としています.
主要な成果:
- 平均して,ヒトのiPSC系は,2つのCNVを発現し,その発祥の線維芽細胞には存在しなかった.
- iPSCにおけるこれらのCNVの50%以上は,親の線維芽細胞における低頻度の体的変異として識別された.
- この研究は,iPSC線が原因ではなく反射していることが示唆され,ヒトの皮膚のソマティック・モザイクが広く存在することを強調しています.
結論:
- iPSCへの再プログラミングは必ずしも de novo CNV を誘導するわけではありません;観察された変異は,しばしばソース組織内の体的モザイクから生じます.
- iPSCのクローン拡張は,起源組織における低頻度CNVの発見のための強力なツールとして機能します.
- 線維芽細胞の約30%に体内のCNVが宿っており,これはヒトの体内の重要なポスチゴティックゲノム不安定性を示している.
関連する概念動画
01:06Induced Pluripotent Stem Cells
Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic cells are...
Somatic cells are...
01:13Induced Pluripotent Stem Cells
Stem cells are undifferentiated cells that divide and produce different types of cells. Ordinarily, cells that have differentiated into a specific cell type are post-mitotic—that is, they no longer divide. However, scientists have found a way to reprogram these mature cells so that they “de-differentiate” and return to an unspecialized, proliferative state. These cells are also pluripotent like embryonic stem cells—able to produce all cell types—and are therefore called induced pluripotent stem...
01:13Induced Pluripotent Stem Cells
Stem cells are undifferentiated cells that divide and produce different types of cells. Ordinarily, cells that have differentiated into a specific cell type are post-mitotic—that is, they no longer divide. However, scientists have found a way to reprogram these mature cells so that they “de-differentiate” and return to an unspecialized, proliferative state. These cells are also pluripotent like embryonic stem cells—able to produce all cell types—and are therefore called induced pluripotent stem...
01:29Somatic to iPS Cell Reprogramming
Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012 for this...
01:32Chromatin Modification in iPS Cells
Chromatin modification alters gene expression; therefore, scientists can add histone-modifying enzymes, histone variants, and chromatin remodeling complexes to somatic cells to aid reprogramming into pluripotent stem (iPS) cells.
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...
01:24Methods of Nuclear Reprogramming
Nuclear reprogramming is a process of transforming one cell type into an unrelated cell type by epigenetic changes that alter the cell’s original gene expression pattern. Such epigenetic changes force cells to express a different set of genes, which play a significant role in inducing transformation into other cell types. Nuclear reprogramming offers applications in reproductive cloning for livestock propagation and regenerative medicine — developing patient-specific cells for injury repair.