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STELLAR Report Summary

Project ID: 305436
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 3 - STELLAR (Stem-cell based therapy for kidney repair)

Project Context and Objectives:
Chronic kidney disease (CKD) affects 8% of the European population and ultimately results in renal failure due to progressive fibrosis. CDK carries a high mortality risk and the number of affected people rises, increasing the demand on renal replacement therapies while the number of available donor organs stays stable.

The STELLAR consortium proposes to develop an alternative to renal replacement therapy, based on the repair capacity of newly discovered kidney mesenchymal stromal cells (kPSCs). By injecting kPSC into affected kidneys, we expect to stop kidney fibrosis and induce tissue repair, ultimately leading to the restoration of normal kidney function.

The STELLAR consortium will:
• develop protocols for up scalable, high quality isolation of kPSCs and precisely characterize kPSC function in comparison to other MSCs.
• test kPSCs in several murine renal disease models, to study their effects on fibrosis and tissue repair.
• discover mechanisms of kidney repair.
• invest in developing the technology necessary for up scaled isolation and quality control.

The STELLAR consortium combines Australian experts on kPSC isolation and characterisation with European experts on renal failure and compounds the state-of-the-art knowledge, facilities and experience needed to develop and validate this novel form of renal therapy. The inclusion of experienced SMEs, with great technical and scientific know-how about assay and protocol development, further strengthens the consortium and will ensure not only the inclusion of new technology, but also a quick translation from bench to clinical application.
Project Results:
The central hypothesis is that kidney stromal cells (kPSCs) confer specific regenerative and homeostatic functions with respect to kidney regeneration as compared to bone marrow derived stromal cells (bmMSC). In the first 18 months we reported on the characterization of MSC derived from various sources. Human kPSC, bmMSC and umbilical cord derived MSC (ucMSC) are phenotypically and functionally similar but differ slightly in in vivo behaviour. We also showed thatkPSC do not fulfill all criteria set for MSC by the ISCT. They do not differentiate into adipocytes, hence from this progress report on these cells will be referred to as human kidney perivascular stromal cells (kPSC).

In the second reporting period the emphasis was on further refining the MSC isolation protocol, toobtain more inside in the mechanistic actions of kidney residing SC and to investigate the potentialof MSC to modulate kidney disease models. We showed that the GMP grade medium developed by partner 8 performed very well, preserving functional characteristics of the various stromal cellsources. In depth mechanistic in vivo studies identified a hitherto unknown plasticity of kPSC withinthe kidney. These cells arise from the collecting duct epithelium, and a portion of cells can undergo EMT to grow as colony forming clonogenic stem cells with MSC properties, but can also revertspecifically to collecting duct when reintroduced to the neonatal kidney. Using the various animal disease models we showed that stromal cells can exert a beneficial effect on limiting podocyte activation and loss, parietal epithelial progenitor (PEC) dysfunction and glomerular endothelial damage. Although in vitro work showed that kPSC have a higher potential with respect to epithelial would healing, no differences were observed between the various stromal cell sources used in these animal experiments.

In this third reporting period the project made some major steps forward with regards to closed system protocol development through the tight collaboration between SME partners 7 and 8. A topo-well concept was developed that allows screening of various compounds for their ability to modulate MSC behaviour. The animal model experiments were finished resulting in important findings with respect to the mechanisms of action of kidney regeneration and the role MSC might play to steer kidney regeneration in the right direction. Both MSC and their conditioned medium were tested in a number of animal models and results showed that conditioned medium of MSC works as well as using the cells themselves. ucMSC and kMSC were shown to have similar positive effects on restoring kidney function in these models and to be superior to bmMSC. kPSC were used in an animal model and were shown to be devoid of tumorigenic potential. Development of the culture process in the bioreactor saw a major boost when different types of micro-carriers were used, resulting in a major increase in the number of cells that can be obtained within a limited timeframe. Progress was achieved in the biomarker studies in which all samples collected in the various animal model experiments were tested for a set of potentially interesting markers.

The consortium continued to actively interact and exchanged knowledge and materials. External dissemination through oral presentations and posters on conferences and through the website and Facebook page continued in this reporting period.

Potential Impact:
The STELLAR consortium strives towards a better understanding of the mechanisms of kidney repair using MSC therapy. Understanding the basic mechanisms of kidney repair using MSC will allow the consortium to translate this knowledge into a clinical product. The consortium will deliver a technology for large scale closed system expansion of MSC based cellular products which will be translated into a clinical protocol and an IMPD for the production of an MSC based cellular therapy for the treatment of patients with renal disease.

Successful implementation of the therapy might have potential impact not only in patient care but also from a health economic and scientific viewpoint. It will impact both industry and SME development in the regenerative medicine field.
An ever increasing number of individuals rely on dialysis for which the direct costs are around 50.000 euro per year. While transplantation is a cost-effective alternative to dialysis, the increasing gap between patients on the waiting list and the shortage in organs available for transplantation will lead to an increase in patients requiring dialysis over the next ten years. This constitutes a huge economic burden to society, with limited therapeutic strategies at the moment. Reducing the requirement for dialysis by even small percentages using MSC, thus would already lead to a major cost reduction in health care expenditure.

With respect to impact on patient wellbeing, clinical application of MSC as a therapy, that can reverse chronic kidney disease is likely to have major impact on wellbeing, quality of life and exercise tolerance of patients with the prospective for societal and labour participation.

STELLAR assembles high level academic institutions in Europe and Australia that combine scientific expertise and knowledge on fundamental and translational research on kidney disease and MSC therapy. From a scientific point of view the collaborative efforts of the consortium will have an impact on the basic understanding of the development of kidney fibrosis, and provide new inside on how to supplement renal repair. The consortium will also strive towards development of a biomarker signature to monitor the effects of cellular renal regeneration therapy. Using a high-throughput biomaterials platform it will search for cues provided by kidney MSC to give them their specific therapeutic potential. The outcome of these studies together with the development of bioreactor technology has the potential to be marketed by the SME’s participating in the consortium.

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