Mesenchymal stromal cell-based therapy in kidney diseases and transplantation

Intense investigation in pre-clinical models of kidney disease and transplantation showed that mesenchymal stromal cell (MSC) therapy acts on renal and inflammatory cells in multiple, complex and integrated ways, resulting in cell repair and regeneration, in the inhibition of inflammatory cells, and in the development of cells endowed with their own anti-inflammatory and immuneregulatory properties. These encouraging data paved the way for exploring the use of MSC in clinics as innovative therapeutic tools for patients with renal diseases and transplantation. In this review, we describe the available results of clinical studies of MSC in patients with post-cardiac surgery, acute kidney injury, chronic kidney diseases - including diabetes, renovascular disease and lupus nephritis - and in kidney transplant recipients, with a particular focus on our experience with MSC therapy as a pro-tolerogenic strategy in kidney transplantation. The available studies, mainly phase 1, indicated that MSC therapy is safe and feasible and not associated with adverse events, at least in the short- and mid-term. Encouraging results have been reported in renovascular disease and kidney transplantation, while studies in acute kidney injury and chronic kidney disease had contrasting outcomes. The relevant issues and the knowledge gap that still limit the translation of MSC cell therapy into clinical practice are discussed briefly

Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis

The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential “circulating factors” contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS

Cellular therapies in organ transplantation

Cellular therapy is a promising tool for improving the outcome of organ transplantation. Various cell types with different immunoregulatory and regenerative properties may find application for specific transplant rejection or injury-related indications. The current era is crucial for the development of cellular therapies. Preclinical models have demonstrated the feasibility of efficacious cell therapy in transplantation, early clinical trials have shown safety of several of these therapies, and the first steps towards efficacy studies in humans have been made. In this review, we address the current state of the art of cellular therapies in clinical transplantation and discuss monitoring tools and endpoints for these studies

Simulations of vesicular disentanglement

As part of the European Horizon 2020 project ACDC, a chemical compiler is being developed that allows the self-assembly of artificial, three-dimensional, vesicular structures to be first simulated and then translated into reality. This work reports on simulations that shed light on an important aspect: How to disentangle inter-vesicular connections

Alpha-synuclein/synapsin III pathological interplay boosts the motor response to methylphenidate

: Loss of dopaminergic nigrostriatal neurons and fibrillary α-synuclein (α-syn) aggregation in Lewy bodies (LB) characterize Parkinson's disease (PD). We recently found that Synapsin III (Syn III), a phosphoprotein regulating dopamine (DA) release with α-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of α-syn aggregation and toxicity. Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind α-syn and controls α-syn-mediated DA overflow and presynaptic compartmentalization. Interestingly, MPH results also efficient for the treatment of attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental psychiatric syndrome associated with Syn III and α-syn polymorphisms and constituting a risk factor for the development of LB disorders. Here, we studied α-syn/Syn III co-deposition and longitudinal changes of α-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) α-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6J wild type (wt) and C57BL/6JOlaHsd α-syn null littermates. Then, we analyzed the locomotor response of these animals to an acute administration of MPH (d-threo) and other MRIs: cocaine, that we previously found to stimulate Syn III-reliant DA release in the absence of α-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate α-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the α-syn conformations stabilized upon MPH binding. We found that only MPH was able to over-stimulate a Syn III-dependent/DAT-independent locomotor activity in the aged SYN120 tg mice showing α-syn/Syn III co-aggregates. MPH enhanced full length (fl) α-syn/Syn III and even more (1-120) α-syn/Syn III interaction in cells exhibiting α-syn/Syn III inclusions. Moreover, in silico studies confirmed that MPH may reduce α-syn fibrillation by stabilizing a protein conformation with increased lipid binding predisposition. Our observations indicate that the motor-stimulating effect of MPH can be positively fostered in the presence of α-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management

Influence of the geometry on the agglomeration of a polydisperse binary system of spherical particles

Within the context of the European Horizon 2020 project ACDC, we intend to develop a probabilistic chemical compiler, to aid the construction of three-dimensional agglomerations of artificial hierarchical cellular constructs. These programmable discrete units offer a wide variety of technical innovations, like a portable biochemical laboratory that e.g. produces macromolecular medicine on demand. For this purpose, we have to investigate the agglomeration process of droplets and vesicles under proposed constraints, like confinement. This paper focuses on the influence of the geometry of the initialization and of the container on the agglomeration

Paths in a network of polydisperse spherical droplets

We simulate the movement and agglomeration of oil droplets in water under constraints, like confinement, using a simplified stochastic-hydrodynamic model. In the analysis of the network created by the droplets in the agglomeration, we focus on the paths between pairs of droplets and compare the computational results for various system sizes

Percolation breakdown in binary and ternary monodisperse and polydisperse systems of spherical particles

We perform computer simulations of an agglomeration process for monodisperse and polydisperse systems of spherical particles in a cylindrical container, using a simplified stochastic-hydrodynamic model. We consider a ternary system with three particle types A, B, and C, in which only connections of the type can be forged, while any other connections with particles of the same type or with C-particles are forbidden, and for comparison a binary system with two particle types A and C, in which only connections of the type can be formed. We study the breakdown of the percolation in the agglomeration at the bottom of the cylinder with an increasing fraction of C-particles

Kauffman Model with spatially separated ligation and cleavage reactions

One of the open questions regarding the origin of life is the problem how macromolecules could be created. One possible answer is the existence of autocatalytic sets in which some macromolecules mutually catalyze each other’s formation. This mechanism is theoretically described in the Kauffman model. We introduce and simulate an extension of the Kauffman model, in which ligation and cleavage reactions are spatially separated in different containers connected by diffusion, and provide computational results for instances with and without autocatalytic sets, focusing on the time evolution of the densities of the various molecules. Furthermore, we study the rich behavior of a randomly generated instance containing an autocatalytic metabolism, in which molecules are created by ligation processes and destroyed by cleavage processes and vice versa or generated and destroyed both by ligation processes

Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review

Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite CD4+ and CD8+ lymphocytes’ reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients’ long-term recovery