Periodic Reporting for period 1 - ALGORITM (Applying human lung tissue models to develop a personalised treatment for critically ill)
Periodo di rendicontazione: 2021-04-01 al 2023-03-31
Recent project focused on to understand the pathophysiology of Acute respiratory distress syndrome (ARDS), which) is a major cause of mortality in the critically ill patients with no effective pharmacological treatment. Recently, two distinct endotypes of ARDS were identified and validated in four large randomized controlled trials: a hyper-inflammatory and a hypo-inflammatory endotype. These endotypes have strikingly different clinical characteristics, biomarker profiles, clinical outcomes, and treatment responses. While these data are highly promising, the biology of these endotypes is not understood. Mesenchymal Stem Cells (MSCs) hold significant therapeutic promise for ARDS and are rapidly progressing to clinical trials across the world. However, concern for the use of stem cells, specifically the risk of tumor formation, remains unresolved. Accumulating evidence suggests that MSCs exert their therapeutic benefit through the release of extracellular vesicles (EVs). MSC EVs are being actively developed as a cell free therapy for ARDS, but for the effective clinical translation it is important to establish EV therapeutic potential for both biological endotypes of patients. In this project, we focused to use cutting edge technology and employ the most physiological human lung tissue models to date to study the biology of ARDS endotypes and to test therapeutic potential of MSC EVs.
The ALGORITM project is an assembly of three scientific and dissemination work packages (WP) aiming to investigate the mechanisms involved in the ARDS pathophysiology in different endotypes and develop an effective personalized therapy for ARDS. We first reveal the lung tissue responses to inflammatory environments and their alterations after EV treatment at single-cell level (WP1). Our second aim was to investigate how ARDS environments alter functional properties of the alveolar epithelial-endothelial barrier and how these alterations are affected by EV treatment (WP2) as the last aim, we investigated how endotype-specific environments alter the metabolism of the primary human pulmonary cells involved in ARDS pathophysiology and how EVs alter these metabolic changes.
In WP1, Through transcriptomic analysis, it was possible to observe that the therapy has different modulatory effects, depending on the cell type, different cells have different metabolism and response, which resulted in different therapeutic responses and immunomodulation. Lung tissue has around 40 different cell types, different cells show different responses. These results will provide the development of an effective and personalized therapy aimed at the main dysfunctions and cell types involved in ARDS.
In WP2, different pharmacological therapeutic responses in patients with ARDS phenotypes, reinforcing the needed to develop a personalized therapy that can cover both phenotypes, even today there is no clinical exam that facilitates this identification. In relation to our therapy, the EVs showed beneficial effects in the Hypo phenotype, however no effects were observed in the hyper phenotype, which led us to question some modifications in the therapy: increasing the dose, multiple applications, changing routes of therapy administration. Some of these questions raised that should be answered in future research, which opened the field for the development of new therapies.
In WP3,the metabolic alterations observed in ARDS are interconnected and can create a vicious cycle, where inflammation and tissue injury further exacerbate metabolic dysfunction, leading to sustained lung injury and organ dysfunction. Understanding the metabolic changes in ARDS is important for identifying potential therapeutic targets and developing interventions that can restore metabolic homeostasis, support tissue repair, and mitigate lung injury.
Dissemination materials such as press releases, and articles have been produced. Additionally, ALGORITM has been presented at conferences, symposium and outreach activities.
In WP1, Through transcriptomic analysis, it was possible to observe that the therapy has different modulatory effects, depending on the cell type, different cells have different metabolism and response, which resulted in different therapeutic responses and immunomodulation. Lung tissue has around 40 different cell types, different cells show different responses. These results will provide the development of an effective and personalized therapy aimed at the main dysfunctions and cell types involved in ARDS.
In WP2, different pharmacological therapeutic responses in patients with ARDS phenotypes, reinforcing the needed to develop a personalized therapy that can cover both phenotypes, even today there is no clinical exam that facilitates this identification. In relation to our therapy, the EVs showed beneficial effects in the Hypo phenotype, however no effects were observed in the hyper phenotype, which led us to question some modifications in the therapy: increasing the dose, multiple applications, changing routes of therapy administration. Some of these questions raised that should be answered in future research, which opened the field for the development of new therapies.
In WP3,the metabolic alterations observed in ARDS are interconnected and can create a vicious cycle, where inflammation and tissue injury further exacerbate metabolic dysfunction, leading to sustained lung injury and organ dysfunction. Understanding the metabolic changes in ARDS is important for identifying potential therapeutic targets and developing interventions that can restore metabolic homeostasis, support tissue repair, and mitigate lung injury.
Dissemination materials such as press releases, and articles have been produced. Additionally, ALGORITM has been presented at conferences, symposium and outreach activities.
This first time pioneering investigation of ARDS endotype-specific microenvironment in human using functional studies in experimental models of ARDS and investigation of metabolic changes in primary pulmonary cells, that will provide unprecedented insight into the human endotype-specific biology so much needed to develop personalised therapy for ARDS patients. Moreover, using the single cell transcriptomics analysis of the lung tissues we provided the most detailed and comprehensive picture of responses to endotype–specific environment of all cell types in the tissue so far, opening new avenues for future studies of immune signalling, molecular basis of susceptibility and development of pathology in ARDS. Therefore my research has strong potential to achieve significant impact to the society. To our knowledge, this was the first study to demonstrate the association between these 3 disorders in ARDS, as this mechanism is not well explored, specifically, in these distinct ARDS phenotypes. Therapy with EVs was able to reverse these changes and prevent the development of premature senescence, however, when using EVs with depleted mitochondria, the effects were lost and no benefit was observed, again, reinforcing that the mitochondrial component is a key component of the EVs effect.