Significant expansion of the donor pool achieved by utilizing islets of variable quality in the production of allogeneic "Neo-Islets", 3-D organoids of Mesenchymal Stromal and islet cells, a novel immune-isolating biotherapy for Type I Diabetes.

Novel biotherapies for Type 1 Diabetes that provide a significantly expanded donor pool and that deliver all islet hormones without requiring anti-rejection drugs are urgently needed. Scoring systems have improved islet allotransplantation outcomes, but their use may potentially result in the waste of valuable cells for novel therapies. To address these issues, we created "Neo-Islets" (NIs), islet-sized organoids, by co-culturing in ultralow adhesion flasks culture-expanded islet (ICs) and Mesenchymal Stromal Cells (MSCs) (x 24 hrs, 1:1 ratio).

Intraperitoneal administration of human "Neo-Islets", 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials.

Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic anti-rejection drugs. Furthermore, the scarcity of pancreas donors and islet transplant failures limit the general availability of such interventions.

Systemic AAV10.COMP-Ang1 rescues renal glomeruli and pancreatic islets in type 2 diabetic mice.

Introduction: Diabetic hyperglycemia causes progressive and generalized damage to the microvasculature. In renal glomeruli, this results in the loss of podocytes with consequent loss of constitutive angiopoietin-1 (Ang1) signaling, which is required for stability of the glomerular endothelium. Repeated tail vein injection of adenovirus expressing COMP-Ang1 (a stable bioengineered form of Ang1) was previously reported to improve diabetic glomerular damage despite the liver and lungs being primary targets of adenoviral infection.

Interim report on the effective intraperitoneal therapy of insulin-dependent diabetes mellitus in pet dogs using "Neo-Islets," aggregates of adipose stem and pancreatic islet cells (INAD 012-776).

We previously reported that allogeneic, intraperitoneally administered "Neo-Islets," composed of cultured pancreatic islet cells co-aggregated with high numbers of immunoprotective and cytoprotective Adipose-derived Stem Cells, reestablished, through omental engraftment, redifferentiation and splenic and omental up-regulation of regulatory T-cells, normoglycemia in autoimmune Type-1 Diabetic Non-Obese Diabetic (NOD) mice without the use of immunosuppressive agents or encapsulation devices. Based on these observations, we are currently testing this Neo-Islet technology in an FDA guided pilot study (INAD 012-776) in insulin-dependent, spontaneously diabetic pet dogs by ultrasound-guided, intraperitoneal administration of 2x10e5 Neo-Islets/kilogram body weight to metabolically controlled (blood glucose, triglycerides, thyroid and adrenal functions) and sedated animals. We report here interim observations on the first 4 canine Neo-Islet-treated, insulin-dependent pet dogs that are now in the early to intermediate-term follow-up phase of the planned 3 year study (> 6 months post treatment).

Durable Control of Autoimmune Diabetes in Mice Achieved by Intraperitoneal Transplantation of "Neo-Islets," Three-Dimensional Aggregates of Allogeneic Islet and "Mesenchymal Stem Cells".

Novel interventions that reestablish endogenous insulin secretion and thereby halt progressive end-organ damage and prolong survival of patients with autoimmune Type 1 diabetes mellitus (T1DM) are urgently needed. While this is currently accomplished with allogeneic pancreas or islet transplants, their utility is significantly limited by both the scarcity of organ donors and life-long need for often-toxic antirejection drugs. Coadministering islets with bone marrow-derived mesenchymal stem cells (MSCs) that exert robust immune-modulating, anti-inflammatory, anti-apoptotic, and angiogenic actions, improves intrahepatic islet survival and function.

Carbamylated Erythropoietin Outperforms Erythropoietin in the Treatment of AKI-on-CKD and Other AKI Models.

Erythropoietin (EPO) may be a beneficial tissue-protective cytokine. However, high doses of EPO are associate with adverse effects, including thrombosis, tumor growth, and hypertension. Carbamylated erythropoietin (CEPO) lacks both erythropoietic and vasoconstrictive actions.

β-MSCs: successful fusion of MSCs with β-cells results in a β-cell like phenotype.

Bone marrow mesenchymal stromal cells (MSC) have anti-inflammatory, anti-apoptotic and immunosuppressive properties and are a potent source for cell therapy. Cell fusion has been proposed for rapid generation of functional new reprogrammed cells. In this study, we aimed to establish a fusion protocol of bone marrow-derived human MSCs with the rat beta-cell line (INS-1E) as well as human isolated pancreatic islets in order to generate insulin producing beta-MSCs as a cell-based treatment for diabetes.

Recent advances in the understanding of acute kidney injury.

Acute kidney injury (AKI) is a common clinical entity associated with high morbidity and mortality and clinical costs. The pathophysiology is multifaceted and involves inflammation, tubular injury, and vascular damage. Recently identified components include necroptosis, a special form of cell death, and autophagy.

Kidney protection and regeneration following acute injury: progress through stem cell therapy.

Acute kidney injury (AKI) is a common clinical entity with high morbidity and mortality rates and ever increasing medical costs. A large number of patients who are hospitalized with morbidities such as diabetes, vascular disease, or chronic kidney disease are at high risk to develop AKI due to ischemic and nephrotoxic insults. The pathophysiology of ischemic and toxic forms of AKI is complex and includes tubular and vascular cell damage and inflammation.

Programmed anti-inflammatory macrophages protect against AKI and promote repair through trophic actions.

Because pharmacological interventions for the treatment of acute kidney injury (AKI) have remained ineffective, cell-based therapies have been developed. Marrow stromal cells have been found to be safe and potentially effective in study subjects. Jung et al.

Design of clinical trials in acute kidney injury: a report from an NIDDK workshop--prevention trials.

AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD.

Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected hospital settings.

AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design.

Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology.

Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients' health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size.

Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials.

Current therapies for acute kidney injury remain primarily supportive and have failed to reduce morbidity, mortality (>50%), and associated costs. This prompted our studies in which rats with bilateral ischemia/reperfusion-induced acute kidney injury were treated with bone marrow-derived, culture-expanded allogeneic mesenchymal stem cells. Their administration into the suprarenal aorta after reflow significantly protected renal function and hastened repair, mediated by complex antiapoptotic, mitogenic, anti-inflammatory, and immune modulating actions that were not elicited by isogeneic fibroblasts.

Role of SDF-1 as a regulatory chemokine in renal regeneration after acute kidney injury.

Both the homing of hematopoietic stem cells (HSCs) to the bone marrow and their engraftment in recipients of bone marrow transplants are primarily mediated by the chemokine stromal-derived factor-1 (SDF-1) or CXCL12, which activates CXCR4, its cognate receptor on HSCs. We showed that the recruitment and temporary attachment of CXCR4-expressing cells, such as HSCs and a fraction of mesenchymal stem cells (MSCs), to the kidney, following ischemia/reperfusion acute kidney injury, are similarly mediated by robustly upregulated SDF-1 in the kidney, indicating that such organ injury appears to lead to the transient expression of a facultative stem cell niche. This SDF-1 response of the injured kidney facilitates both the mobilization from the bone marrow and homing of precursor cells, and other CXCR4-expressing cells such as administered MSCs, to the kidney, where they aid in its protection and repair.

Mesenchymal stromal cells: main factor or helper in regenerative medicine?

Mesenchymal stromal cells (mSCs) are presently studied for the prophylaxis and therapy of a variety of diseases such as acute graft-versus-host disease after allogeneic stem cell transplantation, cardiac indications, bone degeneration, Crohn's disease, and organ rejection, as well as prevention of acute renal failure in high-risk situations. mSCs appear to function through paracrine mechanisms that exert immunosuppressive, anti-inflammatory, anti-apoptotic, mitogenic, and other organ-protective and repair-stimulating actions. mSCs are either cultured in the presence of fetal calf serum (FCS) or platelet lysate (PL).

Earlier diagnosis of acute kidney injury awaits effective therapy.

Novel urinary biomarkers for the early, sensitive, and specific diagnosis of acute kidney injury (AKI) show promise for the improved management of patients with this treatment-resistant complication. Several biomarkers (Kim-1, lipocalin-2, osteopontin, gluthathione S-transferases) that were tested by Rouse et al. during gentamicin-induced AKI and its recovery possess renoprotective activities, capabilities that may guide the development of novel interventions.

The role of multipotent marrow stromal cells (MSCs) in tissue regeneration.

An extensive body of preclinical and clinical data has shown that administration of adult multipotent marrow stromal cells (MSCs) effectively ameliorates experimental and clinical conditions of many different organ systems. Differentiation into organ parenchymal cells, however, is very rare, and the main mechanism for organ protection and regeneration from different types of injury is the exertion of paracrine effects and stimulation of tissue repair. A large number of clinical trials have been conducted and are ongoing to investigate the safety and efficacy of MSCs in different organs after various types of organ injury.

Mesenchymal stem cells: a new therapeutic tool for AKI.

Acute kidney injury (AKI) is a common clinical complication, associated with poor outcomes and the development of chronic kidney disease. Despite major advances in the understanding of its pathophysiology, available therapies for AKI are only supportive; therefore, adequate functional recovery from AKI must predominantly rely on the kidney's own reparative ability. An extensive body of preclinical data from our own and from other laboratories has shown that administration of adult multipotent marrow stromal cells (commonly referred to as mesenchymal stem cells [MSCs]), effectively ameliorates experimental AKI by exerting paracrine renoprotective effects and by stimulating tissue repair.

Limited immune-modulating activity of porcine mesenchymal stromal cells abolishes their protective efficacy in acute kidney injury.

We demonstrated previously that administration of mesenchymal stromal cells (MSCs) after renal ischemia/reperfusion injury (IRI) in rats protected renal function and hastened repair through complex paracrine mechanisms. Here we investigated kidney-protective actions of MSCs in a porcine IRI model that may have relevance to human acute kidney injury (AKI). Groups of female pigs with bilateral IRI were infused with autologous or male allogeneic MSCs.

VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury.

Adult stem cell treatment of complex disorders is a promising therapeutic approach and multipotent marrow stromal cells (MSCs) have been shown to be effective in various animal models of diseases. Acute kidney injury (AKI) is a common and serious problem in hospitalized patients and bone marrow derived multipotent MSCs have been shown to be effective in different models of AKI. The mechanism of action of MSCs is complex but involves paracrine actions including growth factor secretion.