TY - JOUR
T1 - Erythropoietin delivery through kidney organoids engineered with an episomal DNA vector
AU - Du, Z.
AU - Menendez, A. Bas-Cristobal
AU - Urban, M.
AU - Hartley, A.
AU - Ratsma, D.
AU - Koedam, M.
AU - van den Bosch, T. P. P.
AU - Clahsen-van Groningen, M.
AU - Gribnau, J.
AU - Mulder, J.
AU - Reinders, M. E. J.
AU - Baan, C. C.
AU - van der Eerden, B.
AU - Harbottle, R. P.
AU - Hoogduijn, Martin J.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/4/12
Y1 - 2025/4/12
N2 - BackgroundThe kidney's endocrine function is essential for maintaining body homeostasis. Erythropoietin (EPO) is one of the key endocrine factors produced by the kidney, and kidney disease patients frequently experience anemia due to impaired EPO production. In the present study we explored the potential of human induced pluripotent stem cell (iPSC)-derived kidney organoids to restore EPO production.MethodsEPO secretion by kidney organoids was examined under 1% and 20% oxygen levels. To increase the EPO secreting capacity of kidney organoids, iPSC were genetically engineered with a non-integrating scaffold/matrix attachment region (S/MAR) DNA vector containing the EPO gene and generated EPO-overexpressing (EPO+) kidney organoids. To assess the physiological effects of EPO + organoids, 2-8 organoids were implanted subcutaneously in immunodeficient mice.ResultsKidney organoids produced low amounts of EPO under 1% oxygen. EPO S/MAR DNA vectors persisted and continued to robustly express EPO during iPSC expansion and kidney organoid differentiation without interfering with cellular proliferation. EPO + iPSC demonstrated efficient differentiation into kidney organoids. One-month post-implantation, EPO + organoids displayed continuously elevated EPO mRNA levels and significantly increased endothelial cell numbers compared to control organoids. Hematocrit levels were notably elevated in mice implanted with EPO + organoids in an organoid number-dependent manner. EPO + organoids furthermore influenced bone homeostasis in their hosts, evidenced by a change in trabecular bone composition.ConclusionKidney organoids modified by EPO S/MAR DNA vector allow stable long-term delivery of EPO. The observed physiological effects following the implantation of EPO + organoids underscore the potential of gene-edited kidney organoids for endocrine restoration therapy.
AB - BackgroundThe kidney's endocrine function is essential for maintaining body homeostasis. Erythropoietin (EPO) is one of the key endocrine factors produced by the kidney, and kidney disease patients frequently experience anemia due to impaired EPO production. In the present study we explored the potential of human induced pluripotent stem cell (iPSC)-derived kidney organoids to restore EPO production.MethodsEPO secretion by kidney organoids was examined under 1% and 20% oxygen levels. To increase the EPO secreting capacity of kidney organoids, iPSC were genetically engineered with a non-integrating scaffold/matrix attachment region (S/MAR) DNA vector containing the EPO gene and generated EPO-overexpressing (EPO+) kidney organoids. To assess the physiological effects of EPO + organoids, 2-8 organoids were implanted subcutaneously in immunodeficient mice.ResultsKidney organoids produced low amounts of EPO under 1% oxygen. EPO S/MAR DNA vectors persisted and continued to robustly express EPO during iPSC expansion and kidney organoid differentiation without interfering with cellular proliferation. EPO + iPSC demonstrated efficient differentiation into kidney organoids. One-month post-implantation, EPO + organoids displayed continuously elevated EPO mRNA levels and significantly increased endothelial cell numbers compared to control organoids. Hematocrit levels were notably elevated in mice implanted with EPO + organoids in an organoid number-dependent manner. EPO + organoids furthermore influenced bone homeostasis in their hosts, evidenced by a change in trabecular bone composition.ConclusionKidney organoids modified by EPO S/MAR DNA vector allow stable long-term delivery of EPO. The observed physiological effects following the implantation of EPO + organoids underscore the potential of gene-edited kidney organoids for endocrine restoration therapy.
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=eur_pure&SrcAuth=WosAPI&KeyUT=WOS:001465319500005&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1186/s13287-025-04282-w
DO - 10.1186/s13287-025-04282-w
M3 - Article
C2 - 40221815
SN - 1757-6512
VL - 16
JO - STEM CELL RESEARCH & THERAPY
JF - STEM CELL RESEARCH & THERAPY
IS - 1
M1 - 174
ER -
