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Updated: Aug 12, 2025
Author Spotlight: Optimizing iPSC Differentiation for Efficient Production to Generate Kidney Organoids
Published on: September 1, 2023
Inhibition of complement activation by CD55 overexpression in human induced pluripotent stem cell derived kidney
Lonneke H Gaykema1,2, Rianne Y van Nieuwland1, Mette C Dekkers1
1Department of Internal Medicine-Nephrology, Leiden University Medical Center, Leiden, Netherlands.
Abstract:
End stage renal disease is an increasing problem worldwide driven by aging of the population and increased prevalence of metabolic disorders and cardiovascular disease. Currently, kidney transplantation is the only curative option, but donor organ shortages greatly limit its application. Regenerative medicine has the potential to solve the shortage by using stem cells to grow the desired tissues, like kidney tissue. Immune rejection poses a great threat towards the implementation of stem cell derived tissues and various strategies have been explored to limit the immune response towards these tissues. However, these studies are limited by targeting mainly T cell mediated immune rejection while the rejection process also involves innate and humoral immunity. In this study we investigate whether inhibition of the complement system in human induced pluripotent stem cells (iPSC) could provide protection from such immune injury. To this end we created knock-in iPSC lines of the membrane bound complement inhibitor CD55 to create a transplant-specific protection towards complement activation. CD55 inhibits the central driver of the complement cascade, C3 convertase, and we show that overexpression is able to decrease complement activation on both iPSCs as well as differentiated kidney organoids upon stimulation with anti-HLA antibodies to mimic the mechanism of humoral rejection.
Insights
To combat organ shortages for kidney transplantation, researchers explored protecting stem cells from immune rejection. They modified human induced pluripotent stem cells (iPSCs) to inhibit the complement system, reducing immune attack on potential kidney tissues.
Area of Science:
- Regenerative Medicine
- Immunology
- Stem Cell Biology
Background:
- End-stage renal disease (ESRD) is a growing global health concern, with limited donor organs for kidney transplantation.
- Regenerative medicine offers a potential solution by generating kidney tissues from stem cells.
- Immune rejection, particularly T cell-mediated, hinders the clinical application of stem cell-derived tissues, overlooking innate and humoral immunity.
Purpose of the Study:
- To investigate the potential of inhibiting the complement system in human induced pluripotent stem cells (iPSCs) to protect against immune injury.
- To engineer iPSC lines with enhanced expression of the complement inhibitor CD55 for transplant-specific protection.
- To evaluate the efficacy of CD55 overexpression in mitigating complement activation on iPSCs and kidney organoids.
Main Methods:
- Creation of knock-in iPSC lines overexpressing the membrane-bound complement inhibitor CD55.
- Assessment of CD55's ability to inhibit the C3 convertase, a key component of the complement cascade.
- Stimulation of iPSCs and differentiated kidney organoids with anti-HLA antibodies to mimic humoral rejection and measure complement activation.
Main Results:
- Overexpression of CD55 in iPSCs was confirmed.
- CD55 effectively inhibited the C3 convertase, reducing complement activation.
- Reduced complement activation was observed on both iPSCs and kidney organoids when challenged with anti-HLA antibodies.
Conclusions:
- Inhibiting the complement system via CD55 overexpression in iPSCs offers a promising strategy to protect stem cell-derived tissues from humoral immune rejection.
- This approach could enhance the safety and efficacy of regenerative medicine for treating kidney disease.
- Targeting complement activation presents a novel avenue for overcoming immune barriers in transplantation and regenerative therapies.
