Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology.

Latonya J Hickson,Sandra M Herrmann,Bairbre A Mcnicholas,Matthew D Griffin

doi:10.34067/kid.0005692020

Abstract

Drawing from basic knowledge of stem-cell biology, embryonic development, wound healing, and aging, regenerative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical-translational strategies within the field of regenerative medicine, several can be broadly described as promoting disease resolution indirectly through local or systemic interactions with a patient's cells, without permanently integrating or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease-modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associated AKI (SA-AKI), diabetic kidney disease (DKD), and kidney transplantation (KTx). As we describe, the DMRT that has most consistently progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently modulate ischemic, inflammatory, profibrotic, and immune-mediated tissue injury through diverse paracrine mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo-expanded regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury. Other promising DMRT, including adult stem/progenitor cells, stem cell-derived extracellular vesicles, and implantable hydrogels/biomaterials remain at varying preclinical stages of translation for these renal conditions. To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD, or KTx, and clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing knowledge of the pathophysiologic basis for renal-tissue injury and the experience gained from pioneering early-phase clinical trials provide optimism that influential, regenerative treatments for diverse kidney diseases will emerge in the years ahead.

Highlights

Since it was first introduced into biomedical parlance by William Haseltine, the term regenerative medicine has become broadly recognizable to healthcare providers and the general public alike
Well-conducted small- and large-animal model studies have been essential to determining the optimal parameters for clinical application of mesenchymal stem/stromal cells (MSCs) and other diseasemodulating regenerative therapies” (DMRT) to kidney diseases—including the route of delivery and localization after administration; the key responder compartments and cell responses within the kidney; and the source, timing of release, and activity of the most important soluble mediators
In keeping with the literature reviewed in this article, we believe that these critical parameters must be defined for each specific disease and therapy

Summary

Introduction

Since it was first introduced into biomedical parlance by William Haseltine, the term regenerative medicine has become broadly recognizable to healthcare providers and the general public alike. Kidney Transplantation Beyond the “holy grail” of donor-specific tolerance, steady advances in understanding pathologic processes that underlie the common causes of early and late renal allograft failure have revealed other important new therapeutic targets that are not adequately addressed by conventional immunosuppressive drugs and clinical practices [82] These include inflammatory and metabolic pathways that mediate donor-organ injury before and early after transplantation, immunologic processes that drive the formation of donorspecific antibodies and antidonor memory T cells, effector mechanisms responsible for subsequent acute or chronic immune-mediated rejection, and maladaptive cellular processes such as fibrosis and senescence. The trial reports to date support the conclusion that intravenous or intrarenal infusion of MSCs in KTx recipients is safe and associated with comparable early-to-midterm patient/graft outcomes and potentially superior renal function compared with conventional therapeutic regimens Where examined, they provide evidence that pre- or early post-transplant MSC infusions may be associated with favorable immunologic effects, such as increases in circulating T-reg or T-reg/effector T cell ratios. These insights suggest that further integration of in vivo or ex vivo conditioning regimens could improve the success of autologous (and perhaps allogeneic) cell-based DMRT in kidney disease

Conclusions and Future Directions

Haseltine WA

Findings

Nishinakamura R: Human kidney organoids