H2020Индивидуална стипендия2020–2022

ReproXimera · Modelling in vivo lineage reprogramming of human astrocytes into induced neurons in the adult mouse brain

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-02-01 → 2022-04-01
Финансиране от ЕС: 224 934 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Човешките астроцити (поддържащи клетки в мозъка) се изследват за възможността да бъдат превърнати в неврони. Това е важно, за да се разбере как могат да се заменят загубени неврони след наранявания или при невродегенеративни заболявания.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Modelling in vivo lineage reprogramming of human astrocytes into induced neurons in the adult mouse brain

The emergence of reprogramming technologies has revolutionized the classical view of cellular identity as an unchangeable entity. Direct lineage reprogramming enables the fate conversion of one terminally differentiated cell into another demonstrating that changes associated with cellular differentiation are not irreversible. This approach has opened an unprecedented perspective for lost neurons’ replacement following injury and neurodegenerative diseases. In the last decade, successful conversion of murine glial cells into induced neurons has been achieved by transduction with viruses encoding transcription factors that play key role in neurogenesis. More recently, the achievement of in vivo reprogramming of diverse brain cells has opened an unprecedented perspective. However, in vivo reprogramming studies have been restricted to murine glia. Human astroglia reprogramming represents a challenge in the field since it remains unknown whether such lineage reprogramming can also be achieved in vivo in the case of human glia which differs markedly from their rodent counterparts in size and complexity. In this project I have tackled few fundamental questions in the field: First, I have investigated whether human astrocytes can be reprogrammed into induced neurons. Second, I have studied how reprogramming competence of human astrocytes is affected by their maturation stage. Although preliminary, the results obtained in this project show the feasibility of mature human astrocytes reprogramming in vitro.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Studies during last decade have shown that the genetic programs underlying cell identity are plastic even in fully differentiated cells. Direct lineage reprogramming takes advantage of this plasticity to induce cell fate conversions from one cell type into another. The host laboratory is among those who have pioneered successful lineage reprogramming of glial cells into induced functional neurons in vitro and in vivo. These studies have largely focused on murine glia. While there is sparse evidence that also human glia can be reprogrammed into induced neurons, it is unclear whether such lineage conversion can occur within the constraints of the in vivo tissue context by fully integrated mature human glia. In this project I propose an experimental model to study direct lineage reprogramming of human astrocytes into induced neurons at distinct developmental stages within the context of the adult mouse brain in vivo. This model is based on previous findings that show that human astroglial progenitors can integrate into the mouse brain following grafting, maintaining hallmarks that are specific to human astroglia which differ markedly in their complexity from their murine counterparts. Here I will combine this model system with the directed glial differentiation of induced human pluripotent stem cells (hiPSC) and state-of-the-art genome-editing via CRISPR-Cas9 technology. This will enable me to derive transplantable glial progenitors that can be induced to undergo lineage conversion in a humanized in vivo context at distinct maturation stages. With this approach I will obtain important insights into the fundamental question of how the state of maturation and functional integration determines the capacity of human astroglia to undergo lineage conversion into functional neurons in vivo. I expect that the data resulting from this approach will have important implications towards the translation of direct lineage reprogramming into new strategies for brain repair.

Оригинален текст от CORDIS (на английски).

Участници

KING'S COLLEGE LONDON · LondonКоординаторОбединеното кралство