Descrizione del progetto
Progressi nella terapia cellulare renale grazie alle cellule staminali ricavate dall’urina neonatale
La malattia renale cronica, che è provocata dalla perdita di nefroni, causa 1,2 milioni di decessi ogni anno. Le cellule renali derivano da progenitori nefronici della famiglia omologa sine oculis homeobox 2 (SIX2)+, che non sono presenti nel rene maturo. Cellule progenitrici staminali renali (KSPC, kidney stem progenitor cell), che manifestano un’elevata capacità di differenziarsi in cellule epiteliali renali funzionali, sono state scoperte nell’urina di infanti nati prima della conclusione del processo di nefrogenesi. Il progetto NEOGRAFT, finanziato dall’UE, intende stabilire le KSPC quale nuova fonte di precondizionamento di alloinnesti renali in antecedenza al trapianto. A tal fine il progetto chiarirà il profilo immunomodulatorio di tali cellule, nonché il loro potenziale di attecchimento e rigenerazione a livello di singola cellula, e le traccerà nel tessuto avvalendosi di colture di interi organi, con l’obiettivo finale di immunomodulare e rigenerare direttamente il tessuto dei reni.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-ERC - HORIZON ERC GrantsIstituzione ospitante
1081 HV Amsterdam
Paesi Bassi