Christodoulos Xinaris

• PhD
• Coordinator of Research at Mario Negri Institute for Pharmacological Research

Thyroid hormone (TH) signalling is a key modulator of fundamental biological processes that has been evolutionarily con-served in both vertebrate and invertebrate species. TH may have initially emerged as a nutrient signal to convey environmen-tal information to organisms to induce morpho-anatomical changes that could maximise the exploitation of e...

Purpose of review: To discuss existing expectations from organoids and how they can affect biomedical research and society, and to analyse the current limitations and how they can potentially be overcome. Recent findings: Recent success with engineering human organoids has created great enthusiasm and expectations, especially for their potential...

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent, potentially lethal monogenic human disorder. There is currently no cure for ADPKD. The mechanistic complexity of the disease, the absence of animal models that can faithfully mimic the disease, as well as the lack of functional human in vitro assays for compound testing, ha...

Generating kidney organoids using human stem cells could offer promising prospects for research and therapeutic purposes. However, no cell-based strategy has generated nephrons displaying an intact three-dimensional epithelial filtering barrier. Here, we generated organoids using murine embryonic kidney cells, and documented that these tissues reca...

The shortage of transplantable organs provides an impetus to develop tissue-engineered alternatives. Producing tissues similar to immature kidneys from simple suspensions of fully dissociated embryonic renal cells is possible in vitro, but glomeruli do not form in the avascular environment. Here, we constructed renal organoids from single-cell susp...

The advent of Healthcare 4.0 has heralded a disruptive change in medical diagnostics, with Artificial Intelligence (AI) playing a central role in improving diagnostic accuracy and treatment efficacy. This work addresses the integration of AI into medical imaging, specifically through the use of deep learning networks to analyze and segment medical...

Background and Aims Thyroid hormone (TH) signaling plays a crucial role in the regulation of the cell differentiation state, cell cycle and metabolism in various organs. Low TH levels are observed in most patients with chronic kidney disease, and correlate with cell de-differentiation and reactivation of the cell cycle. Despite this knowledge, poss...

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic, rare disease, characterized by the formation of multiple cysts that grow out of the renal tubules. Despite intensive attempts to develop new drugs or repurpose existing ones, there is currently no definitive cure for ADPKD. This is primarily due to the complex and variable pathoge...

Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known, it remains unclear whether its alterations contribute to the pathobiology of diabetic cells. Here, we aim to investigate whether the administration of exogenous T3 can counteract t...

Heart failure affects more than 64 million people worldwide, having a serious impact on their survival and quality of life. Exploring its pathophysiology and molecular bases is an urgent need in order to develop new therapeutic approaches. Thyroid hormone signaling, evolutionarily conserved, controls fundamental biological processes and has a cruci...

Alport syndrome (AS) is a rare disease characterized by defective glomerular basement membranes, caused by mutations in COL4A3, COL4A4, and COL4A5, which synthesize collagen type IV. Patients present with progressive proteinuria, hematuria and podocyte loss. There is currently no cure for Alport syndrome, and this is mainly due to its complex and v...

Insufficient production of erythropoietin (EPO) leads to anaemia. Developing methods for the generation and transplantation of EPO-producing cells would allow scientists to design personalised therapeutic solutions. Here we present a simple and highly reproducible protocol for the generation of neural crest cells (NCCs) that can produce and secrete...

In anamniotes cell loss can typically be compensated for through proliferation, but in amniotes, this capacity has been significantly diminished to accommodate tissue complexity. In order to cope with the increased workload that results from cell death, instead of proliferation highly specialised post-mitotic cells undergo polyploidisation and hype...

Thyroid hormone (TH) signalling is a universally conserved pathway with pleiotropic actions that is able to control the development, metabolism, and homeostasis of organisms. Using evidence from paleoecology/palaeoanthropology and data from the physiology of modern humans, we try to assess the natural history of TH signalling and its role in human...

Abnormal kidney development leads to lower nephron number, predisposing to renal diseases in adulthood. In embryonic kidneys, nephron endowment is dictated by the availability of nephron progenitors, whose self-renewal and differentiation require a relatively repressed chromatin state. More recently, NAD+-dependent deacetylase sirtuins (SIRTs) have...

No effective treatments are available for familial steroid-resistant Focal Segmental Glomerulosclerosis (FSGS), characterized by proteinuria due to ultrastructural abnormalities in glomerular podocytes. Here, we studied a private PAX2 mutation identified in a patient who developed FSGS in adulthood. By generating adult podocytes using patient-speci...

Inadequate production of erythropoietin (EPO) leads to anemia. Although erythropoiesis-stimulating agents can be used to treat anemia, these approaches are limited by high costs, adverse effects, and the need for frequent injections. Developing methods for the generation and transplantation of EPO-producing cells would allow for the creation of per...

Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for ov...

Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. The standard treatments for diabetic patients are glucose and blood pressure control, lipid lowering, and renin-angiotensin system blockade; however, these therapeutic approaches can provide only partial...

Chronic kidney disease is a major global health problem, as it affects 10% of the global population and kills millions of patients every year. It is therefore of the utmost importance to develop models that can help us to understand the pathogenesis of CKD and improve our therapeutic strategies. The discovery of human induced pluripotent stem cells...

Purpose of the review: In this study, we will analyse how diabetes induces the reactivation of organs' developmental programmes and growth, discuss how thyroid hormone (TH) signalling orchestrates these processes, and suggest novel strategies for exploiting TH-mediated reparative and regenerative properties. Recent findings: Diabetes is a global...

The transition from traditional 2D models to three-dimensional (3D) systems represents the most important innovation of the last decades. Numerous studies now employ 3D systems, spheroids and organoids, also based on pluripotent stem cells, for the study of drug toxicity. However, the still high cost of these systems limits their use in xenobiotic...

This commentary highlights the article by Francipane et al that studied the molecular signals supporting kidney vascularization in host lymphoid sites and omenta.

Thyroid hormone (TH) signaling is a universal regulator of metabolism, growth, and development. Here, we show that TH-TH receptor (TH-TR) axis alterations are critically involved in diabetic nephropathy-associated (DN-associated) podocyte pathology, and we identify TRα1 as a key regulator of the pathogenesis of DN. In ZSF1 diabetic rats, T3 levels...

The lack of engineering systems able to faithfully reproduce complex kidney structures in vitro has made it difficult to efficiently model kidney diseases and development. Using polydimethylsiloxane (PDMS) scaffolds and a kidney-derived cell line we developed a system to rapidly engineer custom-made 3D tubules with typical renal epithelial properti...

The growing gap between the number of patients on kidney transplant waiting lists and the number of organs available for transplantation creates a pressing need to find alternative treatments for kidney diseases. Recent methodological advances in developmental biology and stem cell research create intriguing possibilities for generating kidney tiss...

Worldwide, the critical shortage of kidney donors has created an urgent need for tissue-engineered alternatives. A number of tissue engineering strategies combine three-dimensional (3D) culture systems with developmental biology principles to generate de novo kidney tissue. These approaches start with embryonic kidney fragments or kidney progenitor...

Novel methods in developmental biology and stem cell research have made it possible to generate complex kidney tissues in vitro that resemble whole organs and are termed organoids. In this chapter we describe a technique using suspensions of fully dissociated mouse kidney cells to yield organoids that can become vascularized in vivo and mature and...

Supplementary Figures and Tables.

Generating human podocytes in vitro could offer a unique opportunity to study human diseases. Here, we describe a simple and efficient protocol for obtaining functional podocytes in vitro from human induced pluripotent stem cells. Cells were exposed to a three-step protocol, which induced their differentiation into intermediate mesoderm, then into...

Recent technical advances in the stem cell field have enabled the in vitro generation of complex structures resembling whole organs termed organoids. Most of these approaches employ three-dimensional (3D) culture systems that allow stem cell-derived or tissue progenitor cells to self-organize into 3D structures. These systems evolved, methodologica...

New intervention tools for severely damaged kidneys are in great demand to provide patients with a valid alternative to whole organ replacement. For repairing or replacing injured tissues, emerging approaches focus on using stem and progenitor cells. Embryonic kidneys represent an interesting option because, when transplanted to sites such as the r...

Acute kidney injury (AKI) is one of the most relevant health issues, leading to millions of deaths. The magnitude of the phenomenon remarks the urgent need for innovative and effective therapeutic approaches. Cell-based therapy with renal progenitor cells (RPCs) has been proposed as a possible strategy. Studies have shown the feasibility of directi...

The application of cell-based therapies in regenerative medicine is gaining recognition. Here, we show that human bone marrow stromal cells (BMSCs), also known as bone-marrow-derived mesenchymal cells, can be reprogrammed into renal proximal tubular-like epithelial cells using cell-free extracts. Streptolysin-O-permeabilized BMSCs exposed to HK2-ce...

Background: Chronic kidney disease affects 5-7% of people worldwide. The increasing number of patients and the shortage of transplantable organs create an imperative need to develop new methods for generating kidney tissue. Summary: Recent advances in our understanding of the developmental biology of the kidney, along with the establishment of n...

Mesenchymal stem cells (MSCs) of bone marrow origin appear to be an attractive candidate for cell-based therapies. However the major barrier to the effective implementation of MSC-based therapies is the lack of specific homing of exogenously infused cells and overall the inability to drive them to the diseased or damaged tissue. In order to circumv...

Human amniotic fluid stem (hAFS) cells, a novel class of broadly multipotent stem cells that share characteristics of both embryonic and adult stem cells, have been regarded as promising candidate for cell therapy. Taking advantage by the well-established murine model of acute kidney injury (AKI), we studied the proregenerative effect of hAFS cells...

Bone marrow-derived mesenchymal stem cells (BMMSCs) are currently considered one of the cell types with great clinical potential for cell-based therapy. When transplanted systemically, mesenchymal stem cells (MSCs) are able to migrate to sites of injury and exert their therapeutic action via paracrine release of trophic factors instead of a direct...

Thyroid hormone receptor alpha1 (TRalpha1) is predominantly expressed in the myocardium but its biological function under physiological or pathological conditions remains largely unknown. The present study investigated possible interactions between alpha1 adrenergic and thyroid hormone signaling at the level of TRalpha1, potential underlying mechan...

Recent research has revealed novel actions of thyroid hormone (TH) on the heart which may be of important physiological and therapeutic relevance. TH, apart from its "classical" actions on cardiac contractility and heart rhythm, appears to regulate various intracellular signaling pathways related to stress responses and cardiac remodelling. Accumul...

Thyroid hormone has various effects on the cardiovascular system and its effects on cardiac contractility, heart rhythm and vascular function has long been recognized. However, new evidence is emerged on the importance of thyroid hormone in the response of the myocardium to ischaemic stress and cardiac remodelling following myocardial infarction. B...

There is accumulating evidence showing that ischemic preconditioning (PC) may lose its cardioprotective effect in the diseased states. The present study investigated whether PC can be effective in hypothyroidism, a clinical condition which is common and often accompanies cardiac diseases such as heart failure and myocardial infarction. Hypothyroidi...

Cardiac remodeling of viable myocardium occurs after acute myocardial infarction (AMI) and further contributes to cardiac dysfunction. The present study explored whether thyroid hormone (TH) administered shortly after AMI in rats can attenuate cardiac remodeling and improve cardiac function. TH regulates important structural and regulatory proteins...

It is now recognized that changes occurring during cardiac remodeling may influence the tolerance of the myocardium to ischemic stress. Therefore, the present study investigated the response of the post-infarcted heart to ischemia in an experimental model of ischemia and reperfusion injury and the possible underlying mechanisms. Acute myocardial in...

The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction (AMI) with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the TR alpha 1 receptor which is predominant...

It has previously been shown that thyroid hormone can reverse cardiac remodeling in failing hearts by reducing myocardial wall stress due to the unique changes induced in cardiac myocyte shape. This effect may be of therapeutic relevance. Therefore, the present study has investigated potential signaling mechanisms underlying the thyroid hormone act...

It has been previously reported that thyroid hormone receptor alpha1 (TRalpha1) is involved in the regulation of food intake and heart rhythm. Herein, we show that pharmacological inhibition of TRalpha1 by dronedarone, an amiodarone like compound (shown to antagonize thyroid hormone binding to TRalpha1), prevented the thyroid hormone induced increa...

Hyperthyroid hearts are shown to display a phenotype of cardioprotection against ischemic stress, but the underlying signaling mechanisms remain largely unknown. The present study investigated the possible relation of HSP70 to the thyroid hormone induced cardioprotection. HSP70 is a redox-regulated molecular chaperone, and enhances cell survival un...

In the present study we investigated whether acute glucose administration could be protective against hypoxic stress. H9c2 cells were exposed to either 4.5 mM or 22 mM of glucose for 15,min and then were submitted to simulated ischemia. Cell death was microscopically assessed by combined staining with propidium iodide (PI) and Hoeschst 33358. Intra...

There is accumulating evidence that thyroid hormone metabolism is altered after myocardial infarction (AMI) but its physiological relevance remains largely unknown. The present study investigated the possible role of thyroid hormone signaling in the response of the post-infarcted heart to ischaemia-reperfusion. Wistar rats were subjected to left co...

The present study investigated the response of the hypothyroid heart to ischaemia-reperfusion. Hypothyroidism was induced in Wistar rats by oral administration of propylthiouracil (0.05%) for 3 weeks (HYPO rats), while normal animals (NORM) served as controls. Isolated hearts from NORM and HYPO animals were perfused in Langendorff mode and subjecte...