TY - JOUR
T1 - De novo SIX2 activation in human kidneys treated with neonatal kidney stem/progenitor cells
AU - Arcolino, Fanny Oliveira
AU - Hosgood, Sarah
AU - Akalay, Sara
AU - Jordan, Nina
AU - Herman, Jean
AU - Elliott, Tegwen
AU - Veys, Koenraad
AU - Vermeire, Kurt
AU - Sprangers, Ben
AU - Nicholson, Michael
AU - van den Heuvel, Lambertus
AU - Levtchenko, Elena
PY - 2022/12/1
Y1 - 2022/12/1
N2 - During development, nephron structures are derived from a SIX2+ stem cell population. After 36 weeks of gestation, these cells are exhausted, and no new nephrons are formed. We have previously described a non-invasive strategy to isolate and expand the native SIX2+ kidney stem cells from the urine of preterm neonates, named neonatal kidney stem/progenitor cells (nKSPC). Here, we investigated the safety and feasibility of administering nKSPC into human kidneys discarded for transplantation during normothermic machine perfusion (NMP) and evaluated the regenerative and immunomodulatory potential of nKSPC treatment. We found that nKSPC administration during NMP is safe and feasible. Interestingly, nKSPC induced the de novo expression of SIX2 in proximal tubular cells of the donor kidneys and upregulated regenerative markers such as SOX9 and VEGF. This is the first time that SIX2 re-expression is observed in adult human kidneys. Moreover, nKSPC administration significantly lowered levels of kidney injury biomarkers and reduced inflammatory cytokine levels via the tryptophan-IDO-kynurenine pathway. In conclusion, nKSPC is a novel cell type to be applied in kidney-targeted cell therapy, with the potential to induce an endogenous regenerative process and immunomodulation.
AB - During development, nephron structures are derived from a SIX2+ stem cell population. After 36 weeks of gestation, these cells are exhausted, and no new nephrons are formed. We have previously described a non-invasive strategy to isolate and expand the native SIX2+ kidney stem cells from the urine of preterm neonates, named neonatal kidney stem/progenitor cells (nKSPC). Here, we investigated the safety and feasibility of administering nKSPC into human kidneys discarded for transplantation during normothermic machine perfusion (NMP) and evaluated the regenerative and immunomodulatory potential of nKSPC treatment. We found that nKSPC administration during NMP is safe and feasible. Interestingly, nKSPC induced the de novo expression of SIX2 in proximal tubular cells of the donor kidneys and upregulated regenerative markers such as SOX9 and VEGF. This is the first time that SIX2 re-expression is observed in adult human kidneys. Moreover, nKSPC administration significantly lowered levels of kidney injury biomarkers and reduced inflammatory cytokine levels via the tryptophan-IDO-kynurenine pathway. In conclusion, nKSPC is a novel cell type to be applied in kidney-targeted cell therapy, with the potential to induce an endogenous regenerative process and immunomodulation.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85135774546&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35913414
U2 - https://doi.org/10.1111/ajt.17164
DO - https://doi.org/10.1111/ajt.17164
M3 - Article
C2 - 35913414
SN - 1600-6135
VL - 22
SP - 2791
EP - 2803
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 12
ER -