Descrizione del progetto
Promuovere i depuratori cellulari di autorinnovamento in cerca di nuova forza per combattere le infezioni polmonari
I macrofagi, letteralmente «grandi mangiatori», sono un tipo di globuli bianchi che depurano l’organismo da particelle indesiderate, quali agenti patogeni e detriti cellulari. Promuovono l’omeostasi tramite l’eliminazione di microbi e cellule morte, oltre a svolgere funzioni trofiche, di regolazione e di riparazione. I macrofagi di autorinnovamento che risiedono nei tessuti sono una popolazione eterogenea e molti di loro non si sono differenziati nella loro identità cellulare definitiva. Lo stesso ambiente tissutale sembra svolgere un ruolo importante nel fenotipo, con la sua influenza sull’espressione dei geni. Il progetto iPSC2Therapy, finanziato dall’UE, sta studiando la possibilità di integrare i macrofagi alveolari presenti nei polmoni con cellule staminali pluripotenti indotte al fine di controllare il loro potenziale rigenerativo. L’obiettivo finale è rafforzare o scambiare il gruppo dei macrofagi alveolari presenti nell’organismo con quelli integrati nelle cellule staminali, come percorso terapeutico per le infezioni polmonari microbatteriche.
Obiettivo
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.
Campo scientifico
- 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
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
30625 Hannover
Germania