Cell therapy is the new frontier of regenerative medicine. Our laboratory, which has been studying stem cells/precursors of different origins for the treatment of acute and chronic kidney diseases for some time, has recently demonstrated the great therapeutic efficacy of stromal mesenchymal cells isolated from umbilical cord blood in the treatment of kidney diseases. The regenerative action passes through the secretion of biologically active substances and extracellular vesicles which promote regeneration also through the preservation of mitochondria, important organelles controlling the energy metabolism and the antioxidant activities of the cells. This discovery changes our perspective on cell therapies: cells can in fact be vehicles for pro-regenerative substances to the site of damage. Our studies therefore focus on identifying these cellular products and on developing strategies, which include cellular engineering approaches, to increase their therapeutic efficacy.

Our Laboratory has contributed to the understanding of the mechanisms underlying the development of ND. For the first time we demonstrated that during the activation of the complement system - a fundamental element of the immune system - the active protein C3a is generated, an important mediator of renal damage that causes dysfunction and loss of pod cells at the glomerular level. In experimental ND models we have shown that treatment with a C3a receptor antagonist improves renal function and preserves the structure of the glomerulus by protecting the integrity of mitochondria in podocytes. These data are an important starting point for the development of innovative therapies for ND care. We also demonstrated that the binding of C5a, one of the terminal products of complement activation, with its receptor on endothelial cells is responsible for the loss of the anti-thrombotic properties of endothelium in patients with HUS.

The aim of this line of research is to understand whether complement proteins, which are fundamental elements of our immune system, can be mediators of damage and possible therapeutic targets in thrombotic microangiopathies, such as haemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (PTT). We have developed an ex vivo assays that allowed us to discover that in HUS and PTT there is uncontrolled activation of the complement at the endothelial level, which leads to the formation of thrombi in the microcirculation. This assay allows us to monitor both the activity of the disease, differentiating between the acute phase and remission, and to test the effectiveness of the drug treatment patients receive. Furthermore, with this test we are evaluating the activity of new drugs that inhibit complement at the endothelial level.

In response to the COVID-19 pandemic, the laboratory investigated the cellular mechanisms activated by SARS-CoV-2 in vitro that leads to the endothelial damage that underlies the thrombotic phenomena that frequently occur in patients with severe forms of COVID-19. Specifically, the laboratory has shown that exposure of microvascular endothelial cells to SARS-CoV-2 spike 1 (S1) protein induced the expression of the adhesive molecule ICAM-1 and von Willebrand Factor, which associated with inflammatory cell adhesion and thrombus formation, respectively. In this context, complement activation plays a key role in exacerbating S1-induced endothelial damage and inhibitors of the complement system are effective in limiting S1-induced endothelial damage. The laboratory is also developing an in vivo model with human ACE2 transgenic mice to evaluate how S1 injection can induce acute lung injury characterized by endothelial damage and complement activation. As part of the COVID-19 pandemic, the Laboratory was responsible for identifying in vitro cellular mechanisms activated by SARS-cov-2 that lead to endothelial damage, the basis of thrombotic phenomena that occur frequently in patients with severe forms. Specifically, the Laboratory has demonstrated that the exposure of the spike protein 1 (S1) of SARS-cov-2 is able to induce on the surface of the endothelial cells of the microcirculation the expression of the adhesive molecule ICAM-1 and von Willebrand Factor (vwf), proteins associated respectively with the adhesion of inflammatory cells and the formation of thrombus. In this context, complement activation plays a key role in exacerbating endothelial damage induced by S1 and inhibitors of the different pathways of complement activation have been shown to be effective in preventing such damage. The Laboratory is also developing an in vivo model with transgenic mice expressing human ACE2 to evaluate how the protein S1 is able to induce acute lung damage characterized by endothelial damage and complement activation.

As part of the scientific response to the COVID-19 pandemic, the laboratory investigated the spread of SARS-CoV-2 through the use of serological tests and antigenic swabs to identify the presence of specific antibodies to different viral various proteins or the genetic material of the virus in the population of the province of Bergamo, one of the most affected during the first pandemic wave of March 2020. More recently, the laboratory is monitoring how the immune protection guaranteed by vaccination evolves over time both in terms of humoral immunity, neutralizing antibodies with the ability to block viral infection in cultured cells, as well as the cellular immunity provided by memory T and B cells.