Mesenchymal Stem Cells for Acute Kidney Injury: Can the Body’s Own Repair Cells Save Failing Kidneys?
Introduction
Every year, acute kidney injury strikes approximately one in five hospitalized adults worldwide — a sudden, often catastrophic loss of renal function caused by ischemia, sepsis, nephrotoxic drugs, or surgical complications. In its severe forms, AKI carries mortality rates exceeding 50% in intensive care settings, and even patients who survive face a dramatically elevated lifetime risk of chronic kidney disease, end-stage renal failure, and cardiovascular death.
Kidney disease, including acute kidney injury (AKI) and chronic kidney disease (CKD), is a significant global public health problem, with incidence and mortality rates increasing in recent decades. AKI is experienced by one fifth of all adults and one third of all children worldwide.
The kidney has a remarkable — but limited — capacity for self-repair. After mild to moderate injury, surviving tubular cells can dedifferentiate, proliferate, and repopulate the damaged epithelium. After severe injury, this intrinsic repair capacity is overwhelmed, and permanent nephron loss leads to progressive renal impairment. Mesenchymal stem cells (MSCs) — multipotent stromal cells found in bone marrow, adipose tissue, and multiple other sources — have emerged as one of the most promising tools to augment this repair response: not by replacing damaged cells, but by creating the biological environment in which the kidney’s own surviving cells can regenerate most effectively.
The work of Reza Moghadasali and colleagues at the Royan Institute for Stem Cell Biology and Technology, Tehran — among Iran’s most productive stem cell research groups — has contributed fundamental preclinical evidence establishing MSC therapy’s mechanisms and efficacy in AKI models, paving the way for clinical translation.
What Are Mesenchymal Stem Cells?
Definition and Sources
Mesenchymal stem cells (MSCs) are derived from a diverse range of human tissues. They are multipotent and have immunomodulatory effects to assist in the recovery from tissue injury and the inhibition of inflammation.
MSCs are defined by three criteria established by the International Society for Cell and Gene Therapy (ISCT):
- Plastic-adherent growth in standard culture conditions
- Expression of surface markers CD73, CD90, CD105 (positive) and CD45, CD34, CD14, CD11b, CD79α, CD19, HLA-DR (negative)
- Capacity to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro
MSC sources relevant to kidney therapy:
| Source | Advantages | Disadvantages |
| Bone marrow | Most studied; well-characterized | Invasive harvest; donor site morbidity |
| Adipose tissue | Abundant; minimally invasive harvest | Slightly different immunophenotype |
| Umbilical cord (Wharton’s jelly) | Non-invasive collection; young cells | Allogeneic (immune considerations) |
| Urine-derived | Non-invasive; renal origin cells | Lower yield; less characterized |
| Amniotic fluid | Fetal source; high potency | Complex collection |
Human adipose tissue has been used as a source for MSCs in peritoneal dialysis patients. In one phase I trial, autologous adipose-derived MSCs were infused systemically in PD patients, demonstrating feasibility and safety.
How MSCs Help the Injured Kidney: The Paracrine Revolution
Beyond Differentiation: The Paracrine Paradigm
Early MSC research hypothesized that stem cells worked by differentiating into the cell types of damaged organs — becoming new kidney tubular cells to replace those destroyed by AKI. This hypothesis has been largely superseded:
The regenerative effects of MSCs do not rely on their differentiation and ability to replace damaged tissues, but are primarily mediated by the paracrine release of factors, including extracellular vesicles (EVs), composed of microvesicles and exosomes.
MSCs engraft minimally — typically less than 1% of administered cells are found in the damaged kidney at 48 hours. Yet functional kidney recovery is dramatic. The explanation lies in the MSC secretome: the constellation of growth factors, cytokines, and extracellular vesicles that MSCs release when they sense injury signals, which collectively reprogram the local environment toward repair.
Key Paracrine Mechanisms
Anti-inflammatory signaling: Mesenchymal stem cells (MSCs) are one option for the treatment of AKI due to their physiological activities related to inflammation, apoptosis, angiogenesis, and immunomodulation. The administration of MSCs has been shown to improve renal function and protect against tubular injury in a mouse model of AKI. This was accompanied by an increase in M2 macrophage infiltration and the conversion of activated macrophages to an anti-inflammatory phenotype.
MSCs shift macrophage polarization from the pro-inflammatory M1 phenotype (producing TNF-α, IL-1β, IL-6) to the anti-inflammatory M2 phenotype (producing IL-10, TGF-β) — converting the post-AKI inflammatory milieu from tissue-damaging to tissue-repairing.
Tubular cell protection: Moghadasali et al. demonstrated that mesenchymal stem cell-conditioned medium accelerates regeneration of human renal proximal tubule epithelial cells after gentamicin toxicity, establishing that factors secreted by MSCs directly protect tubular cells without requiring direct cell-cell contact.
Key MSC-secreted protective factors include:
- IGF-1 (insulin-like growth factor 1): promotes tubular cell survival and proliferation
- HGF (hepatocyte growth factor): anti-apoptotic; promotes tubular regeneration
- VEGF (vascular endothelial growth factor): promotes peritubular capillary repair — critical because peritubular capillary loss drives AKI-to-CKD transition
- SDF-1 (stromal cell-derived factor 1): recruits endogenous progenitor cells to the injury site
Extracellular vesicle-mediated repair: MSC-derived EVs contain genetic and protein material that upon transferring to recipient cells can activate several repair mechanisms to ameliorate renal injury. Recent studies have shown that MSC-derived EV therapy improved renal outcomes in several animal models of AKI and CKD, including ischemia-reperfusion injury, drug/toxin-induced nephropathy, renovascular disease, ureteral obstruction, and subtotal nephrectomy.
Exosomes carrying micro-RNAs (miR-let7c, miR-30, miR-21) modulate TGF-β signaling in tubular cells — reducing fibrogenic gene expression and preventing the AKI-to-CKD transition.
The Royan Institute’s Preclinical Research Program
From Rodents to Non-Human Primates
The Royan Institute’s MSC kidney research program — with Reza Moghadasali as a central contributor — has systematically moved from in vitro models through rodent models to primate models, providing the translational ladder required for clinical application:
In vitro work: Moghadasali’s work on MSC-conditioned medium protecting human renal proximal tubule epithelial cells from gentamicin toxicity established the paracrine mechanism in a human cell system — providing mechanistic proof of concept without requiring animal studies.
Rodent AKI models: cisplatin-induced AKI, ischemia-reperfusion injury, and gentamicin nephrotoxicity — the three most widely used preclinical AKI models — all showed MSC-mediated functional improvement in creatinine clearance, tubular histology, and inflammatory marker reduction.
Non-human primate models: Moghadasali et al. performed intra-renal arterial injection of autologous bone marrow MSCs in a rhesus Macaca mulatta model of cisplatin-induced AKI, demonstrating safety and functional improvement at a scale approximating human kidney anatomy and physiology — the critical bridge study before clinical trials.
CKD fibrosis prevention: Autologous transplantation of MSCs tended to prevent progress of interstitial fibrosis in a rhesus Macaca mulatta monkey model of chronic kidney disease — suggesting MSC therapy may be relevant not only for AKI rescue but for slowing CKD progression.
Clinical Translation: From Bench to Bedside
The Iranian Clinical Trial Program
Results of animal trials showed that mesenchymal stem cell treatment has been found to be a good treatment for acute kidney injury. The treatment was not very effective in treating chronic kidney disease, but helps prevent progression of acute kidney injury to advanced chronic kidney injury.
Building on this preclinical foundation, Royan Institute researchers in collaboration with Iranian nephrology centers have conducted Phase I clinical trials:
Bone marrow MSCs in ADPKD: Makhlough et al. (including Moghadasali) demonstrated the safety and tolerability of autologous bone marrow mesenchymal stromal cells in autosomal dominant polycystic kidney disease patients — establishing the safety profile in a CKD population.
Bone marrow MSCs in CKD: Makhlough, Shekarchian, Moghadasali et al. reported bone marrow mesenchymal stromal cell infusion in patients with chronic kidney disease in a safety study with 18 months of follow-up — demonstrating acceptable safety with no major adverse events, paving the way for efficacy trials.
Adipose-derived MSCs in peritoneal dialysis: A prospective open-label Phase I trial evaluated the safety of single intravenous infusion of autologous adipose-derived MSCs in peritoneal dialysis patients with ultrafiltration failure — another Royan-led trial advancing the clinical safety database.
Challenges on the Path to Clinical Practice
What Must Be Resolved
Despite compelling preclinical data and promising early clinical safety results, several major challenges must be resolved before MSC therapy becomes standard clinical practice for AKI:
Dose and timing optimization: the optimal MSC dose, timing relative to injury, and route of administration (intravenous systemic, intra-renal arterial, intra-peritoneal) remain incompletely defined. Numerous studies have investigated the feasibility, safety, and efficacy of MSC-based therapies for kidney disease. Although the exact mechanism of MSC-based therapy remains uncertain, their therapeutic value in the treatment of a diverse range of kidney diseases has been studied in clinical trials.
Manufacturing and quality: large-scale GMP-compliant MSC production requires consistency across batches — challenging given MSCs’ biological variability between donors and passages.
Identifying responders: not all AKI patients or etiologies respond equally to MSC therapy — developing biomarkers that predict which patients will benefit most is essential for clinical trial success.
Exosome-based approaches: Several challenges need to be addressed as we move towards clinical translation. To date, the primary uncertainties for MSC-derived EV therapy for renal disease include insufficient scientific data to support their safety, and the need to identify the most appropriate EV cellular source, isolation method, and dose regimen.
Conclusion
Mesenchymal stem cell therapy for acute kidney injury represents one of nephrology’s most exciting translational frontiers — grounded in compelling biology, supported by robust preclinical evidence across multiple AKI models including primate studies, and now entering the clinical trial phase with an acceptable safety profile documented in Iranian and international cohorts.
The Royan Institute’s research program — with Reza Moghadasali as a key scientific contributor — has exemplified the rigorous translational approach required to move stem cell therapy from petri dish to patient: building from in vitro paracrine mechanisms through rodent models to primate AKI studies and Phase I clinical safety trials in CKD, ADPKD, and dialysis patients.
Your next steps as a patient with kidney disease, clinician, or researcher:
- Stay informed about active clinical trials: ClinicalTrials.gov and the Iranian Registry of Clinical Trials (IRCT) both list active MSC kidney studies — patients with AKI or progressive CKD who meet eligibility criteria may be candidates for enrollment
- Understand the current status: MSC therapy for AKI is not yet standard clinical practice — it remains investigational, and patients should not pursue unregulated commercial MSC treatments outside formal clinical trial settings
- If you are a nephrologist, recognize the AKI-to-CKD transition as the key target for intervention — the evidence suggests MSC therapy is most effective in preventing this transition, rather than reversing established CKD fibrosis
- Support translational research funding — the gap between compelling primate AKI data and adequately powered Phase III clinical trials is primarily a funding gap; advocacy for stem cell research investment directly accelerates clinical availability
- Monitor the extracellular vesicle/exosome literature — MSC-derived exosomes may ultimately prove more practical than whole cell therapy, avoiding the complexity of live cell manufacturing, storage, and administration while retaining therapeutic potency
- Consider that the Royan Institute’s work exemplifies a broader lesson: Iran’s investment in stem cell research infrastructure has produced internationally competitive science with direct clinical translation potential — a model for other middle-income countries developing translational research capacity