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From iPSC-Macrophage Biology Towards Regenerative Therapies Targeting Respiratory Infections

Project description

Encouraging self-renewing cellular scavengers to find new strength to fight lung infections

Macrophages, literally 'large eaters', are a type of white blood cell that cleans the body of unwanted particles including pathogens and cellular debris. They promote homeostasis through the clearance of microbes and dead cells and execute trophic, regulatory and repair functions. Self-renewing tissue-resident macrophages are a heterogeneous population, and many of them have not differentiated into their final cellular identity. The tissue environment itself seems to play a major role in phenotype, influencing the expression of genes. The EU-funded iPSC2Therapy project is investigating the ability to integrate alveolar macrophages found in the lungs with induced pluripotent stem cells to control their regenerative potential. The end goal is to enhance or exchange the body's alveolar macrophage pool with the stem cell-integrated ones as a route to therapy for mycobacterial lung infections.

Objective

Tissue resident macrophages (TRMs) can be found in various organs and fulfil important functions in host defence and tissue homeostasis. Recent studies in the murine system suggest profound tissue plasticity and self-renewal capacity of TRMs, rendering this cell population highly suitable for new cell-based therapies. Mycobacterial infections represent a serious health problem, for which new therapies are highly needed. Given the important role of alveolar macrophages (MΦs) in pulmonary host defence, I propose a cutting-edge MΦ based therapy using induced pluripotent stem cell (iPSC) technology. The unique features of iPSC will allow to investigate important regulators for the development and regenerative potential of human MΦs with the overall aim to apply these cells as an innovative treatment for pulmonary (non)tuberculous mycobacterial infections. I go beyond current knowledge and envision to enhance or exchange the endogenous alveolar MΦ cell pool by iPSC-MΦs, thereby introducing a completely new cell therapy concept. This ground-breaking cell transfer concept will have broad application potential to combat life threatening infectious diseases of the lower respiratory tract and may even be expanded to Mycobacterium tuberculosis infections. Using different knock-out iPSC lines, I will unravel important regulators for the regenerative potential of iPSC-MΦs following intra-pulmonary transfer. State-of the-art genome editing will be combined with innovative single cell RNAseq tools to understand and enhance the regenerative properties of human iPSC-MΦs. Using established cell depletion and cell transfer techniques, I will decipher the therapeutic potential of mature human iPSC-derived MΦ in vitro and in vivo using humanized mouse models and pre-clinical mycobacterial infections scenarios. The iPSC2Therapy proposal will provide an innovative anti-mycobacterial treatment with broad implications to infectious diseases and beyond.

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Topic(s)

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Funding Scheme

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ERC-STG - Starting Grant

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Call for proposal

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(opens in new window) ERC-2019-STG

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Host institution

MEDIZINISCHE HOCHSCHULE HANNOVER
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 499 100,00
Address
Carl-Neuberg-Strasse 1
30625 Hannover
Germany

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Region
Niedersachsen Hannover Region Hannover
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 499 100,00

Beneficiaries (1)

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