Projektbeschreibung
Stammzellen aus dem Urin von Neugeborenen bringen Nierenzelltherapie voran
Chronisches Nierenversagen, das durch den Verlust von Nephronen verursacht wird, fordert jährlich 1,2 Millionen Menschenleben. Nierenzellen entstehen aus sine oculis homeobox homolog 2 (SIX2)+ Nephronvorläuferzellen, die in der ausgewachsenen Niere nicht vorhanden sind. Allerdings wurden im Urin von vor der vollständigen Nephrogenese geborenen Neugeborenen Nierenstamm-/Vorläuferzellen (nKSPCs) entdeckt, die eine hohe Differenzierungsfähigkeit zu funktionellen Nierenepithelzellen aufweisen. Das EU-finanzierte Projekt NEOGRAFT zielt darauf ab, nKSPCs als neuartige Quelle für die Vorkonditionierung von Nierentransplantaten vor der Verpflanzung zu etablieren. Zu diesem Zweck wird NEOGRAFT das immunmodulatorische Profil von nKSPCs und deren Transplantations- und Regenerationspotenzial auf Einzelzellebene aufklären und sie in Geweben unter Verwendung von Ganzorgan-Kulturen verfolgen, um letztendlich Nierengewebe direkt immunmodulieren und regenerieren zu können.
Ziel
Global mortality from chronic kidney disease (CKD) is estimated at more than 1.2 million annually. CKD is caused by the irreversible loss of nephrons, the structural and functional units of the kidney. Lineage tracing revealed that all renal cells are derived from a SIX2+ embryonic progenitor population originating at the cap mesenchyme (CM). SIX2 is essential for cells’ self-renewal, and its cessation signals the initiation of nephron differentiation. However, SIX2+ progenitor cells are exhausted in the mature kidney.
My team has recently discovered a novel unique source of kidney stem/progenitor cells (nKSPCs) derived from the urine of neonates born before the completion of nephrogenesis. nKSPCs express SIX2 as well as various other CM progenitor markers, and they show a high capacity to differentiate into functional kidney epithelial cells. Additionally, our data show that nKSPCs have an immunomodulatory capacity in vitro. Using normothermic machine perfusion (NMP) of human kidneys, we have discovered that nKSPCs are able to reduce inflammatory responses and activate regenerative processes.
Building on these findings, I aim to establish nKSPCs as a potent novel cell type for the development of kidney-targeted cell therapy for preconditioning kidney allografts prior to transplantation. To this end, I will elucidate the immunomodulatory profile of nKSPCs and demonstrate their potential for engraftment and regeneration at single cell level using advanced methodologies for the first time in this field. Moreover, I will use the ground-breaking pre-clinical platform of whole organ culture system to trace single nKSPCs in kidney tissue over a longer period of time after injection.
nKSPCs are an unexplored progenitor cell type, which might revolutionize the field of kidney diseases.
My long-term goal is to establish clinical-grade nKSPCs for the development of kidney-targeted cell therapy with the capacity to directly immunomodulate and regenerate kidney tissue.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-ERC - HORIZON ERC GrantsGastgebende Einrichtung
1081 HV Amsterdam
Niederlande