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.
Fields of science
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health scienceshealth sciencesinfectious diseases
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsgenomes
- medical and health sciencesbasic medicinephysiologyhomeostasis
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
30625 Hannover
Germany