Regenerative Medicine and Immunomodulatory Therapy: Insights From the Kidney, Heart, Brain, and Lung

Pino, Christopher J.; Westover, Angela J.; Johnston, Kimberly A.; Buffington, Deborah A.; Humes, H. David

doi:10.1016/j.ekir.2017.12.012

Cited by 28 publications

(46 citation statements)

References 79 publications

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“…At present, the development of cell tissue engineering and regenerative medicine is particularly rapid. Many scholars are committed to applying this theory to the treatment of renal failure [8]. Because cell therapy is relatively simple to perform, stem cells isolated from their own tissues have fewer side effects in the course of treatment, and its clinical application value is particularly extensive [9].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Loaded with Gelatin Microcryogels Attenuate Renal Fibrosis

Geng

Hong

Chi

et al. 2019

BioMed Research International

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Background The treatment of chronic kidney diseases (CKDs) by different approaches using mesenchymal stem cells (MSCs) has made great strides. In this study, we aimed to explore the potential mechanism of gelatin microcryogels (GMs) as a cell therapeutic vector to block the progression of CKD. Methods In vivo, the pedicled omentum valve with MSC-loaded GMs was packed onto 5/6 nephrectomized kidneys derived from rats. The therapeutic effects were evaluated. In vitro, TNF-α, TGF-β, and MSCs were added to the medium of the HK-2 cell culture system, and key genes involved in anti-inflammatory and antifibrosis effects were evaluated by qPCR. Results After 12 weeks of MSC transplantation, kidney functions, such as serum creatinine, urea nitrogen, and 24-hour urine protein, were significantly improved. The pedicled omentum valve was packed with MSC-loaded GMs onto the 5/6 nephrectomized kidney, and the expressions of collagen IV, α-SMA, and TGF-β were all evaluated by immunohistochemical staining and western blot analysis. MSC-loaded-GMs also showed antifibrotic effects by inducing the upregulation of HO-1, BMP-7, and HGF and the downregulation of MCP-1 at the mRNA level. Four weeks after MSC-loaded GM treatment, we found that the mRNA levels of TNF-α and IL-6 were clearly reduced. MSC-conditional medium (MSC-CM) showed that the TNF-α-induced expression of IL-8 and IL-6 mRNA was reversed; E-cadherin mRNA was upregulated; and the TGF-β-induced expression of collagen IV, α-SMA, and fibronectin (FN) mRNA in HK-2 cells was reduced. Conclusions We demonstrated that the pedicled omentum valve packed with MSC-loaded GMs had a renal protective effect on the 5/6 nephrectomized kidney by observing the anti-inflammatory and antifibrosis effects.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Loaded with Gelatin Microcryogels Attenuate Renal Fibrosis

Geng

Hong

Chi

et al. 2019

BioMed Research International

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“…Indeed, BM MSC-based regenerative medicine approaches are being developed to treat CKD, aiming to halt progression of fibrosis by vascular regeneration, stimulate kidney regeneration, or enhance immunomodulation after renal transplantation. These therapies include administration of cells or products secreted by cells [9][10][11]. BM MSCs are an effective treatment for CKD in a range of preclinical animal models [12].…”

Section: Introductionmentioning

confidence: 99%

Paracrine Proangiogenic Function of Human Bone Marrow-Derived Mesenchymal Stem Cells Is Not Affected by Chronic Kidney Disease

Rhijn-Brouwer

Balkom

Papazova

et al. 2019

Stem Cells International

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Background. Cell-based therapies are being developed to meet the need for curative therapy in chronic kidney disease (CKD). Bone marrow- (BM-) derived mesenchymal stromal cells (MSCs) enhance tissue repair and induce neoangiogenesis through paracrine action of secreted proteins and extracellular vesicles (EVs). Administration of allogeneic BM MSCs is less desirable in a patient population likely to require a kidney transplant, but potency of autologous MSCs should be confirmed, given previous indications that CKD-induced dysfunction is present. While the immunomodulatory capacity of CKD BM MSCs has been established, it is unknown whether CKD affects wound healing and angiogenic potential of MSC-derived CM and EVs. Methods. MSCs were cultured from BM obtained from kidney transplant recipients (N=15) or kidney donors (N=17). Passage 3 BM MSCs and BM MSC-conditioned medium (CM) were used for experiments. EVs were isolated from CM by differential ultracentrifugation. BM MSC differentiation capacity, proliferation, and senescence-associated β-galactosidase activity was assessed. In vitro promigratory and proangiogenic capacity of BM MSC-derived CM and EVs was assessed using an in vitro scratch wound assay and Matrigel angiogenesis assay. Results. Healthy and CKD BM MSCs exhibited similar differentiation capacity, proliferation, and senescence-associated β-galactosidase activity. Scratch wound migration was not significantly different between healthy and CKD MSCs (P=0.18). Healthy and CKD BM MSC-derived CM induced similar tubule formation (P=0.21). There was also no difference in paracrine regenerative function of EVs (scratch wound: P=0.6; tubulogenesis: P=0.46). Conclusions. Our results indicate that MSCs have an intrinsic capacity to produce proangiogenic paracrine factors, including EVs, which is not affected by donor health status regarding CKD. This suggests that autologous MSC-based therapy is a viable option in CKD.

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“…The precise mechanism of action of the SCD is becoming better understood and appears to be an immunomodulatory process which inhibits leukocyte activation, The low iCa 2+ environment during RCA and the low shear stress along the blood pathway within the SCD promotes a selective binding of the most activated neutrophils and monocytes to the membranes of the device. 24,28,41 This selectivity is due to the calcium dependency of leukocyte binding processes. Once bound, the activated neutrophils are promoted in the low iCa 2+ environment to transition from delayed apoptosis to an apoptotic program and released back to the systemic circulation.…”

Section: Discussionmentioning

confidence: 99%

Use of the Selective Cytopheretic Device in Critically Ill Children

Goldstein

Askenazi

Basu

et al. 2021

Kidney International Reports

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Introduction Critically ill children with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT) are at increased risk of death. The selective cytopheretic device (SCD) promotes an immunomodulatory effect when circuit ionized calcium (iCa 2+ ) is maintained at <0.40 mmol/l with regional citrate anticoagulation (RCA). In a randomized trial of adult patients on CRRT, those treated with the SCD maintaining an iCa 2+ <0.40 mmol/l had improved survival/dialysis independence. We conducted a US Food and Drug Administration (FDA)–sponsored study to evaluate safety and feasibility of the SCD in 16 critically ill children. Methods Four pediatric intensive care units (ICUs) enrolled children with AKI and multiorgan dysfunction receiving CKRT to receive the SCD integrated post-CKRT membrane. RCA was used to achieve a circuit iCa 2+ level <0.40 mmol/l. Subjects received SCD treatment for 7 days or CKRT discontinuation, whichever came first. Results The FDA target enrollment of 16 subjects completed the study from December 2016 to February 2020. Mean age was 12.3 ± 5.1 years, weight was 53.8 ± 28.9 kg, and median Pediatric Risk of Mortality II was 7 (range 2–19). Circuit iCa 2+ levels were maintained at <0.40 mmol/l for 90.2% of the SCD therapy time. Median SCD duration was 6 days. Fifteen subjects survived SCD therapy; 12 survived to ICU discharge. All ICU survivors were dialysis independent at 60 days. No SCD-related adverse events (AEs) were reported. Conclusion Our data demonstrate that SCD therapy is feasible and safe in children who require CKRT. Although we cannot make efficacy claims, the 75% survival rate and 100% renal recovery rate observed suggest a possible favorable benefit-to-risk ratio.

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Regenerative Medicine and Immunomodulatory Therapy: Insights From the Kidney, Heart, Brain, and Lung

Cited by 28 publications

References 79 publications

Mesenchymal Stem Cells Loaded with Gelatin Microcryogels Attenuate Renal Fibrosis

Mesenchymal Stem Cells Loaded with Gelatin Microcryogels Attenuate Renal Fibrosis

Paracrine Proangiogenic Function of Human Bone Marrow-Derived Mesenchymal Stem Cells Is Not Affected by Chronic Kidney Disease

Use of the Selective Cytopheretic Device in Critically Ill Children

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