Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM).

SIGNIFICANCE STATEMENT: Mesenchymal stromal cells (MSCs) may offer a novel therapy for diabetic kidney disease (DKD), although clinical translation of this approach has been limited. The authors present findings from the first, lowest dose cohort of 16 adults with type 2 diabetes and progressive DKD participating in a randomized, placebo-controlled, dose-escalation phase 1b/2a trial of next-generation bone marrow-derived, anti-CD362 antibody-selected allogeneic MSCs (ORBCEL-M). A single intravenous (iv) infusion of 80×10 6 cells was safe and well-tolerated, with one quickly resolved infusion reaction in the placebo group and no subsequent treatment-related serious adverse events (SAEs). Compared with placebo, the median annual rate of decline in eGFR was significantly lower with ORBCEL-M, although mGFR did not differ. The results support further investigation of ORBCEL-M in this patient population in an appropriately sized phase 2b study. BACKGROUND: Systemic therapy with mesenchymal stromal cells may target maladaptive processes involved in diabetic kidney disease progression. However, clinical translation of this approach has been limited. METHODS: The Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study, a randomized, placebo-controlled phase 1b/2a trial, assesses safety, tolerability, and preliminary efficacy of next-generation bone marrow-derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) in adults with type 2 diabetes and progressive diabetic kidney disease. This first, lowest dose cohort of 16 participants at three European sites was randomized (3:1) to receive intravenous infusion of ORBCEL-M (80×10 6 cells, n =12) or placebo ( n =4) and was followed for 18 months. RESULTS: At baseline, all participants were negative for anti-HLA antibodies and the measured GFR (mGFR) and estimated GFR were comparable between groups. The intervention was safe and well-tolerated. One placebo-treated participant had a quickly resolved infusion reaction (bronchospasm), with no subsequent treatment-related serious adverse events. Two ORBCEL-M recipients died during follow-up of causes deemed unrelated to the trial intervention; one recipient developed low-level anti-HLA antibodies. The median annual rate of kidney function decline after ORBCEL-M therapy compared with placebo did not differ by mGFR, but was significantly lower by eGFR estimated by the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Immunologic profiling provided evidence of preservation of circulating regulatory T cells, lower natural killer T cells, and stabilization of inflammatory monocyte subsets in those receiving the cell therapy compared with placebo. CONCLUSIONS: Findings indicate safety and tolerability of intravenous ORBCEL-M cell therapy in the trial's lowest dose cohort. The rate of decline in eGFR (but not mGFR) over 18 months was significantly lower among those receiving cell therapy compared with placebo. Further studies will be needed to determine the therapy's effect on CKD progression. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrial.gov NCT02585622 .

Health-related quality of life in patients with steroid-refractory acute graft-versus-host disease.

BACKGROUND: Evidence regarding health-related quality of life (HRQoL) in patients with steroid-refractory acute graft-versus-host disease (SR-aGvHD) is lacking. Evaluating HRQoL was a secondary objective of the HOVON 113 MSC trial. Here we describe the outcomes of the EQ-5D-5L, EORTC QLQ-C30, and FACT-BMT for all adult patients who completed these questionnaires at baseline (i.e., before the start of treatment; n = 26). METHODS: Descriptive statistics were used to describe baseline patient and disease characteristics, EQ-5D dimension scores and values, EQ VAS scores, EORTC QLQ-C30 scale/item and summary scores, and FACT-BMT subscale and total scores. RESULTS: The mean EQ-5D value was 0.36. In total, 96% of the patients reported problems with usual activities, 92% with pain/discomfort, 84% with mobility, 80% with self-care, and 72% with anxiety/depression. The mean EORTC QLQ-C30 summary score was 43.50. Mean scale/item scores ranged from 21.79 to 60.00 for functioning scales, from 39.74 to 75.21 for symptom scales, and from 5.33 to 91.67 for single items. The mean FACT-BMT total score was 75.31. Mean subscale scores ranged from 10.09 for physical well-being to 23.94 for social/family well-being. CONCLUSION: Our study showed that HRQoL in patients with SR-aGvHD is poor. Improving HRQoL and symptom management in these patients should be a top priority.

A unique immune signature in blood separates therapy-refractory from therapy-responsive acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is an immune cell‒driven, potentially lethal complication of allogeneic hematopoietic stem cell transplantation affecting diverse organs, including the skin, liver, and gastrointestinal (GI) tract. We applied mass cytometry (CyTOF) to dissect circulating myeloid and lymphoid cells in children with severe (grade III-IV) aGVHD treated with immune suppressive drugs alone (first-line therapy) or in combination with mesenchymal stromal cells (MSCs; second-line therapy). These results were compared with CyTOF data generated in children who underwent transplantation with no aGVHD or age-matched healthy control participants. Onset of aGVHD was associated with the appearance of CD11b+CD163+ myeloid cells in the blood and accumulation in the skin and GI tract. Distinct T-cell populations, including TCRγδ+ cells, expressing activation markers and chemokine receptors guiding homing to the skin and GI tract were found in the same blood samples. CXCR3+ T cells released inflammation-promoting factors after overnight stimulation. These results indicate that lymphoid and myeloid compartments are triggered at aGVHD onset. Immunoglobulin M (IgM) presumably class switched, plasmablasts, and 2 distinct CD11b- dendritic cell subsets were other prominent immune populations found early during the course of aGVHD in patients refractory to both first- and second-line (MSC-based) therapy. In these nonresponding patients, effector and regulatory T cells with skin- or gut-homing receptors also remained proportionally high over time, whereas their frequencies declined in therapy responders. Our results underscore the additive value of high-dimensional immune cell profiling for clinical response evaluation, which may assist timely decision-making in the management of severe aGVHD.

Cytokine Mixtures Mimicking the Local Milieu in Patients with Inflammatory Bowel Disease Impact Phenotype and Function of Mesenchymal Stromal Cells.

Locally applied mesenchymal stromal cells (MSCs) have the capacity to promote the healing of perianal fistulas in Crohn's disease (CD) and are under clinical development for the treatment of proctitis in ulcerative colitis (UC). Despite these clinical advances, the mechanism of action of local MSC therapy in inflammatory bowel disease (IBD) is largely unknown. We hypothesized that the local cytokine environment in IBD patients affects the immunomodulatory properties of MSCs. To evaluate this, 11 cytokines were analyzed in inflamed tissues obtained from CD and UC patients. Based on the identified cytokine profiles 4 distinct cytokine mixtures that mimic various inflammatory IBD environments were established. Next, MSCs were cultured in the presence of either of these 4 cytokine mixtures after which the expression of immunomodulatory and tissue regenerative molecules and the capacity of MSCs to modulate T-cell proliferation and dendritic cell (DC) differentiation were assessed. Our data show that MSCs respond, in a cytokine-specific manner, by upregulation of immunomodulatory and tissue regenerative molecules, including cyclooxygenase-2, indoleamine 2,3-dioxygenase, and transforming growth factor-ß1. Functional studies indicate that MSCs exposed to a cytokine profile mimicking one of the 2 UC cytokine milieus were less effective in inhibition of DC differentiation. In conclusion, our data indicate that cytokine mixes mimicking the local cytokine milieus of inflamed UC colonic or CD fistulas tissues can differentially affect the immunomodulatory and tissue regenerative characteristics of MSCs. These data support the hypothesis that the local intestinal cytokine milieu serves as a critical factor in the efficacy of local MSC treatment.

Autologous bone marrow-derived mesenchymal stromal cell therapy with early tacrolimus withdrawal: The randomized prospective, single-center, open-label TRITON study.

After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.

Human leukocyte antigen selected allogeneic mesenchymal stromal cell therapy in renal transplantation: The Neptune study, a phase I single-center study.

Mesenchymal stromal cells (MSC) hold promise as a novel immune-modulatory therapy in organ transplantation. First clinical studies have used autologous MSCs; however, the use of allogeneic "off-the-shelf" MSCs is more sustainable for broad clinical implementation, although with the risk of causing sensitization. We investigated safety and feasibility of allogeneic MSCs in renal transplantation, using a matching strategy that prevented repeated mismatches. Ten patients received two doses of 1.5 × 106 /kg allogeneic MSCs 6 months after transplantation in a single-center nonrandomized phase Ib trial, followed by lowering of tacrolimus (trough level 3 ng/mL) in combination with everolimus and prednisone. Primary end point was safety, measured by biopsy proven acute rejection (BPAR) and graft loss 12 months after transplantation. Immune monitoring was performed before and after infusion. No BPAR or graft loss occurred and renal function remained stable. One patient retrospectively had DSAs against MSCs, formed before infusion. No major alterations in T and B cell populations or plasma cytokines were observed upon MSC infusion. Administration of HLA selected allogeneic MSCs combined with low-dose tacrolimus 6 months after transplantation is safe at least in the first year after renal transplantation. This sets the stage to further explore the efficacy of third-party MSCs in renal transplantation.

Cytokine-induced hematopoietic stem and progenitor cell mobilization: unraveling interactions between stem cells and their niche.

Peripheral blood hematopoietic stem and progenitor cells (HSPCs), mobilized by granulocyte colony-stimulating factor, are widely used as a source for both autologous and allogeneic stem cell transplantation. The use of mobilized HSPCs has several advantages over traditional bone marrow-derived HSPCs, including a less invasive harvesting process for the donor, higher HSPC yields, and faster hematopoietic reconstitution in the recipient. For years, the mechanisms by which cytokines and other agents mobilize HSPCs from the bone marrow were not fully understood. The field of stem cell mobilization research has advanced significantly over the past decade, with major breakthroughs in the elucidation of the complex mechanisms that underlie stem cell mobilization. In this review, we provide an overview of the events that underlie HSPC mobilization and address the relevant cellular and molecular components of the bone marrow niche. Furthermore, current and future mobilizing agents will be discussed.

Long-term Evaluation of Allogeneic Bone Marrow-derived Mesenchymal Stromal Cell Therapy for Crohn's Disease Perianal Fistulas.

BACKGROUND AND AIMS: The long-term safety and efficacy of allogeneic bone marrow-derived mesenchymal stromal cell [bmMSC] therapy in perianal Crohn's disease [CD] fistulas is unknown. We aimed to provide a 4-year clinical evaluation of allogeneic bmMSC treatment of perianal CD fistulas. METHODS: A double-blind dose-finding study for local bmMSC therapy in 21 patients with refractory perianal fistulising Crohn's disease was performed at the Leiden University Medical Center in 2012-2014. All patients treated with bmMSCs [1 x 107 bmMSCs cohort 1, n = 5; 3 × 107 bmMSCs cohort 2, n = 5; 9 × 107 bmMSCs cohort 3, n = 5] were invited for a 4-year evaluation. Clinical events were registered, fistula closure was evaluated, and anti-human leukocyte antigen [HLA] antibodies were assessed. Patients were also asked to undergo a pelvic magnetic resonance imaging [MRI] and rectoscopy. RESULTS: Thirteen out of 15 patients [87%] treated with bmMSCs were available for long-term follow-up. Two non-MSC related malignancies were observed. No serious adverse events thought to be related to bmMSC therapy were found. In cohort 2 [n = 4], all fistulas were closed 4 years after bmMSC therapy. In cohort 1 [n = 4] 63%, and in cohort 3 [n = 5] 43%, of the fistulas were closed, respectively. In none of the patients anti-HLA antibodies could be detected 24 weeks and 4 years after therapy. Pelvic MRI showed significantly smaller fistula tracts after 4 years. CONCLUSIONS: Allogeneic bmMSC therapy for CD-associated perianal fistulas is also in the long-term a safe therapy. In bmMSC-treated patients, fistulas with closure at Week 24 were still closed after 4 years.

Preparing for cell culture scale-out: establishing parity of bioreactor- and flask-expanded mesenchymal stromal cell cultures.

BACKGROUND: Cell-based therapies have the potential to become treatment options for many diseases, but efficient scale-out of these therapies has proven to be a major hurdle. Bioreactors can be used to overcome this hurdle, but changing the culture method can introduce unwanted changes to the cell product. Therefore, it is important to establish parity between products generated using traditional methods versus those generated using a bioreactor. METHODS: Mesenchymal stromal cells (MSCs) are cultured in parallel using either traditional culture flasks, spinner vessels or a new bioreactor system. To investigate parity between the cells obtained from different methods, harvested cells are compared in terms of yield, phenotype and functionality. RESULTS: Bioreactor-based expansion yielded high cell numbers (222-510 million cells). Highest cell expansion was observed upon culture in flasks [average 5.0 population doublings (PDL)], followed by bioreactor (4.0 PDL) and spinner flasks (3.3 PDL). Flow cytometry confirmed MSC identity (CD73+, CD90+ and CD105+) and lack of contaminating hematopoietic cell populations. Cultured MSCs did not display genetic aberrations and no difference in differentiation and immunomodulatory capacity was observed between culture conditions. The response to IFNγ stimulation was similar for cells obtained from all culture conditions, as was the capacity to inhibit T cell proliferation. CONCLUSIONS: The new bioreactor technology can be used to culture large amounts of cells with characteristics equivalent to those cultured using traditional, flask based, methods.

Hypercholesterolemia affects cardiac function, infarct size and inflammation in APOE*3-Leiden mice following myocardial ischemia-reperfusion injury.

BACKGROUND: Hypercholesterolemia is a major risk factor for ischemic heart disease including acute myocardial infarction. However, long-term effects of hypercholesterolemia in a rodent myocardial ischemia-reperfusion injury model are unknown. Therefore, the effects of diet-induced hypercholesterolemia on cardiac function and remodeling were investigated up to eight weeks after myocardial ischemia-reperfusion (MI-R) injury which was induced in either normocholesterolemic (NC-MI) or hypercholesterolemic (HC-MI) APOE*3-Leiden mice. METHODS: Left ventricular (LV) dimensions were serially assessed using parasternal long-axis echocardiography followed by LV pressure-volume measurements. Subsequently, infarct size and the inflammatory response were analyzed by histology and fluorescence-activated cell sorting (FACS) analysis. RESULTS: Intrinsic LV function eight weeks after MI-R was significantly impaired in HC-MI compared to NC-MI mice as assessed by end-systolic pressure, dP/dtMAX, and -dP/dtMIN. Paradoxically, infarct size was significantly decreased in HC-MI compared to NC-MI mice, accompanied by an increased wall thickness. Hypercholesterolemia caused a pre-ischemic peripheral monocytosis, in particular of Ly-6Chi monocytes whereas accumulation of macrophages in the ischemic-reperfused myocardium of HC-MI mice was decreased. CONCLUSION: Diet-induced hypercholesterolemia caused impaired LV function eight weeks after MI-R injury despite a reduced post-ischemic infarct size. This was preceded by a pre-ischemic peripheral monocytosis, while there was a suppressed accumulation of inflammatory cells in the ischemic-reperfused myocardium after eight weeks. This experimental model using hypercholesterolemic APOE*3-Leiden mice exposed to MI-R seems suitable to study novel cardioprotective therapies in a more clinically relevant animal model.

FOXO3, a Molecular Search for the Fountain of Youth.

FOXO3 has been consistently associated with longevity and with a reduction in the prevalence of cardiovascular disease. In this issue, Yan et al. (2019) report that FOXO3-activated vascular cells derived from human embryonic stem cells (ESCs) promote multiple vascular functions and reverse cellular aging through the transcriptional repression of CSRP1.

Chronic kidney failure mineral bone disorder leads to a permanent loss of hematopoietic stem cells through dysfunction of the stem cell niche.

In chronic kidney disease (CKD), endothelial injury, is associated with disease progression and an increased risk for cardiovascular complications. Circulating cells with vascular reparative functions are hematopoietic and also reduced in CKD. To explore the mechanistic basis behind these observations, we have investigated hematopoietic stem cell (HSC) homeostasis in a mouse model for non-progressive CKD-mineral and bone disorder with experimentally induced chronic renal failure (CRF). In mice subjected to 12 weeks of CRF, bone marrow HSC frequencies were decreased and transplantation of bone marrow cells from CRF donors showed a decrease in long-term HSC repopulation compared to controls. This loss was directly associated with a CRF-induced defect in the HSC niche affecting the cell cycle status of HSC and could not be restored by the PTH-reducing agent cinacalcet. In CRF, frequencies of quiescent (G0) HSC were decreased coinciding with an increase in hematopoietic progenitor cells (HPC) in the S-and G2-phases of cell cycle. Moreover, in CRF mice, HSC-niche supporting macrophages were decreased compared to controls concomitant to impaired B lymphopoiesis. Our data point to a permanent loss of HSC and may provide insight into the root cause of the loss of homeostatic potential in CKD.

No Clinical Benefit of Intramuscular Delivery of Bone Marrow-derived Mononuclear Cells in Nonreconstructable Peripheral Arterial Disease: Results of a Phase-III Randomized-controlled Trial.

BACKGROUND AND AIMS: Prospects for no-option, end-stage peripheral artery disease (PAD) patients remain poor. Although results from open and semiblinded studies fuel hope for cell-based strategies in no-option patients, so far conclusions from the available placebo-controlled studies are not supportive. With the intention to end the remaining controversy with regard to cell therapy for PAD we conducted a confirmatory, double-blinded randomized placebo-controlled phase 3 trial. STUDY DESIGN: This randomized controlled trial was registered (NCT00539266). Inclusion criteria included stable or progressive disabling PAD, no imminent need for amputation, absent accepted options for revascularization. Diabetic disease was an exclusion criterion. Bone marrow (500-700 mL) was harvested and bone marrow-derived mononuclear cells were concentrated to 40 mL. Concentrated cells or placebo (diluted blood) were intramuscularly injected at 40 locations of the calf muscle. RESULTS: Fifty-four patients (mean (sd) age 58.2 (14.2) yrs, 58% males) were randomized. Twenty-eight patients received BM-MNCs, 26 placebo. Baseline criteria were similar in the 2 groups. No significant differences were observed for the primary (number of amputations, (pain free) walking distance) and secondary outcome parameters (ankle brachial index, pain scores, quality of life (SF-36)). DISCUSSION: This fully blinded replication trial of autologous BM-MNC fails to confirm a benefit for cell therapy in no-option PAD patients, consequently BM-MNC therapy should not be offered as a clinical treatment. Apparent contrasting conclusions from open and controlled studies underscore the importance of a controlled trial design in evaluating cell-based interventions in PAD.

Mesenchymal stromal cells induce a permissive state in the bone marrow that enhances G-CSF-induced hematopoietic stem cell mobilization in mice.

Mesenchymal stromal cells (MSCs) support hematopoietic stem cells (HSCs) in vivo and enhance HSC engraftment and hematopoietic recovery upon cotransplantation with HSCs. These data have led to the hypothesis that MSCs may affect the HSC niche, leading to changes in HSC retention and trafficking. We studied the effect of MSC administration on the HSC compartment in the bone marrow (BM) in mice. After injection of MSCs, HSC numbers in the BM were decreased coinciding with an increased cell cycle activity compared with phosphate-buffered saline (PBS)-injected controls. Furthermore, the frequency of macrophages was significantly reduced and niche factors including Cxcl12, Scf, and Vcam were downregulated in endosteal cells. These BM changes are reminiscent of events associated with granulocyte colony-stimulating factor (G-CSF)-induced hematopoietic stem and progenitor cell (HSPC) mobilization. Interestingly, coadministration of MSCs and G-CSF resulted in a twofold increase in peripheral blood HSPC release compared with injection of G-CSF alone, whereas injection of MSCs alone did not induce HSPC mobilization. After intravenous administration, MSCs were only observed in the lungs, suggesting that they exert their effect on the HSC niche through a soluble mediator. Therefore, we tested the hypothesis that MSC-derived extracellular vesicles (EVs) are responsible for the observed changes in the HSC niche. Indeed, administration of EVs resulted in downregulation of Cxcl12, Scf, and Vcam and enhanced G-CSF-induced HSPC mobilization at similar levels as MSCs and G-CSF. Together, these data indicate that MSCs induce a permissive state in the BM, enhancing HSPC mobilization through the release of EVs.

Safety and efficacy of percutaneous intramyocardial bone marrow cell injection for chronic myocardial ischemia: Long-term results.

BACKGROUND: Intramyocardial injection of bone marrow cells (BMC) in refractory angina patients with chronic myocardial ischemia has shown to be safe and improve clinical status during short-term follow-up. However, scarce data are available on long-term (>12 months) safety and efficacy. Therefore, the occurrence of clinical events and the long-term clinical effects of intramyocardial BMC injection were evaluated in patients with chronic myocardial ischemia up to 10 years after treatment. METHODS AND RESULTS: Patients (n = 100, age 64 ± 9 years, male 88%) with chronic myocardial ischemia who underwent intramyocardial BMC injection between 2004 and 2010 were evaluated. During yearly outpatient clinic visits, the occurrence of clinical events was documented. In addition, clinical status was assessed according to the Canadian Cardiovascular Society (CCS) score and quality of life was measured using the Seattle Angina Questionnaire. These parameters were evaluated at baseline and during the first year, followed by cross-sectional long-term follow-up which was performed in 2011 and 2014. No adverse events considered related to the procedure occurred during 10 years of follow-up. Observed annual mortality rate and annual myocardial infarction rate were 3.8% and 1.9% per year, respectively. When compared to baseline, CCS class and quality of life remained significantly better during 5-year follow-up after BMC treatment (both P < 0.05). CONCLUSIONS: The present long-term follow-up study shows that intramyocardial BMC injection in patients with chronic myocardial ischemia is safe and improves both angina complaints and quality of life up to 5 years after BMC treatment.

Clinical-Grade Isolated Human Kidney Perivascular Stromal Cells as an Organotypic Cell Source for Kidney Regenerative Medicine.

Mesenchymal stromal cells (MSCs) are immunomodulatory and tissue homeostatic cells that have shown beneficial effects in kidney diseases and transplantation. Perivascular stromal cells (PSCs) identified within several different organs share characteristics of bone marrow-derived MSCs (BM-MSCs). These PSCs may also possess tissue-specific properties and play a role in local tissue homeostasis. We hypothesized that human kidney-derived PSCs (hkPSCs) would elicit improved kidney repair in comparison with BM-MSCs. Here we introduce a novel, clinical-grade isolation method of hkPSCs from cadaveric kidneys by enriching for the perivascular marker, NG2. hkPSCs show strong transcriptional similarities to BM-MSCs but also show organotypic expression signatures, including the HoxD10 and HoxD11 nephrogenic transcription factors. Comparable to BM-MSCs, hkPSCs showed immunosuppressive potential and, when cocultured with endothelial cells, vascular plexus formation was supported, which was specifically in the hkPSCs accompanied by an increased NG2 expression. hkPSCs did not undergo myofibroblast transformation after exposure to transforming growth factor-ß, further corroborating their potential regulatory role in tissue homeostasis. This was further supported by the observation that hkPSCs induced accelerated repair in a tubular epithelial wound scratch assay, which was mediated through hepatocyte growth factor release. In vivo, in a neonatal kidney injection model, hkPSCs reintegrated and survived in the interstitial compartment, whereas BM-MSCs did not show this potential. Moreover, hkPSCs gave protection against the development of acute kidney injury in vivo in a model of rhabdomyolysis-mediated nephrotoxicity. Overall, this suggests a superior therapeutic potential for the use of hkPSCs and their secretome in the treatment of kidney diseases. Stem Cells Translational Medicine 2017;6:405-418.