Research

1) To understand the effect of a persistent inflammatory context to the development of a cardinal form of organ failure: fibrosis.

Different inflammatory cell types and mediators are known to contribute to the development of Idiopathic Pulmonary Fibrosis (IPF). Recently, specific subsets of macrophages have been identified as profibrotic cellular players contributing to myofibroblast differentiation in the lung. During aging, chronic, sterile, low-grade inflammation – called inflammaging – develops, which contributes to the pathogenesis of age-related diseases such as IPF. In other words, inflammaging is the long-term result of the chronic physiological stimulation of the innate immune system, which can become damaging during aging. A condition associated with aging and with a defective innate immune response is clonal hematopoiesis (CH: accumulation of somatic mutations in hematopoietic cells in healthy people). The frequency of CH increases with age and it has been associated with the development of cardiovascular disease. Together with the laboratory of Dr. Borja Saez (CIMA, Pamplona), we are exploring the role of clonal hematopoiesis in the development of chronic lung disease including IPF and COPD.

2) To find out mechanisms involved in COVID-19 disease.

We are currently exploring not only the factors why SARS-CoV2 infection give rise to severe COVID-19 disease vs. mild/moderate form of the disease, but also the consequences of the infection including the study of which are the mechanisms of injury following infection, and how to promote regeneration of damaged tissue. In severe cases of the disease, hyperinflammation takes place and the release of exaggerated amounts of proinflammatory cytokines affect many other tissues, leading to not only respiratory failure but multiorgan failure. Thus, there is an urgent need to understand the mechanisms involved in the pathogenesis of SARS-CoV2 infection to circumvent damages in the organism and a fatal outcome. We also propose that the presence of clonal hematopoiesis may predict the progression to a severe disease. This study is performed together with the laboratory of Dr. Borja Saez.

3) To study epithelial-mesenchymal interactions in the development of pulmonary fibrosis.

We have identified a previously unrecognized mechanism involved in lung fibrosis. We have found that a subpopulation of fibroblasts exhibits Notch3 activity at homeostasis and that this activation increases following injury being detected in myofibroblasts and suggesting an implication in fibrogenesis. Our findings demonstrate that Notch3 deficiency attenuates pulmonary fibrosis and impedes lung function decline through a mechanism by which Notch3 regulates the survival and differentiation of fibroblasts. Currently, we are studying the source of the Notch signal and whether a similar mechanism occurs in human IPF by using cutting-edge imaging technology and genetic modulation. Thus, our work may reveal novel molecular targets for future anti-fibrotic therapeutic approaches.

4) To investigate how airway stem cells maintain a functional immune ecosystem.

We have discovered an essential cellular interaction between airway stem cells and a newly identified immune cell localized within the airway epithelium. This close proximity between both cell types allows them to communicate through the Notch pathway. In the absence of the Notch signal, these immune cells are lost and the initiation of an allergen-induced immune response is affected thus suggesting the relevance of these cells in allergic asthma and the implication of airway stem cells in regulating the immune system.

5) To promote tissue repair by stimulating lung stem cells.

Alveolar type (AT) 2 cells function as epithelial stem cells of the adult lung. We have identified a novel subpopulation of AT2 cells that may contribute to repair after injury. In last years, novel epithelial subpopulations have been found to appear following injury and to contribute to tissue regeneration. We are currently characterizing the subset identified in our laboratory by using genomics technology and organoid cultures to evaluate their stemness features and regenerative capacities, as well as using different in vivo models of injury to test these properties.

6) To unravel the mechanisms involved in pulmonary hypertension (PH).

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by vascular remodelling of small arteries of the pulmonary vasculature, causing thickening of the vascular wall and luminal occlusion by vSMC and endothelial cell proliferation, slowing blood flow and increasing pulmonary arterial pressure which can lead to right ventricular failure and death. Thus, understanding the mechanisms underlying the development of PAH will contribute to find novel targets to resolve the damage in the lung and the heart. We study the cellular communication between endothelial cells and vSMC using in vivo models of PH and in vitro co-cultures to investigate the mechanisms involved in the excessive vSMC proliferation and (de)differentiation from the contractile to the synthetic phenotype. It has been demonstrated the important role of Notch3 in these pathological processes. Thus, we are inhibiting Notch3 signaling in vSMC genetically and pharmacologically to test its impact in PAH. These studies are performed in collaboration with Dr. Jesus Ruiz-Cabello (CICbiomaGUNE, San Sebastian).

1) To understand the effect of a persistent inflammatory context to the development of a cardinal form of organ failure: fibrosis.

Different inflammatory cell types and mediators are known to contribute to the development of Idiopathic Pulmonary Fibrosis (IPF). Recently, specific subsets of macrophages have been identified as profibrotic cellular players contributing to myofibroblast differentiation in the lung. During aging, chronic, sterile, low-grade inflammation – called inflammaging – develops, which contributes to the pathogenesis of age-related diseases such as IPF. In other words, inflammaging is the long-term result of the chronic physiological stimulation of the innate immune system, which can become damaging during aging. A condition associated with aging and with a defective innate immune response is clonal hematopoiesis (CH: accumulation of somatic mutations in hematopoietic cells in healthy people). The frequency of CH increases with age and it has been associated with the development of cardiovascular disease. Together with the laboratory of Dr. Ana Pardo-Saganta (CIMA, Pamplona), we are exploring the role of clonal hematopoiesis in the development of chronic lung disease including IPF and COPD.

2) To find out mechanisms involved in COVID-19 disease.

Severe COVID-19 disease courses with an overwhelming inflammatory response causing acute respiratory distress syndrome (ARDS) that may lead to not only respiratory failure but multiorgan failure and death. A dysfunctional immune system is suspected to be the cause of an exaggerated inflammatory response that triggers the cytokine storm involved in fatal COVID-19 cases. In addition, most critical cases of COVID-19 disease occurs mainly in older people (those aged over 60 years), and people with co-morbidities. Since clonal hematopoiesis is associated with aging and with an aberrant innate immune response, we propose that its presence contributes to COVID-19 severity increasing the risk of developing or worsen the ARDS-associated cytokine storm and death in patients with SARS-Cov2 infection. Our observations will help to predict which patients are going to rapidly progress to a life-threatening disease allowing an early therapeutic intervention. This study is performed together with the laboratory of Dr. Ana Pardo-Saganta.

3) To develop a non-genotoxic conditioning regimens for hematopoietic stem cell transplantation in Ataxia Telangiectasia (In collaboration with AEFAT)

Hematopoietic stem cell transplantation (HSCT) can alleviate the hematopoietic-associated alterations that occur in Ataxia Telangiectasia (AT).  Nonetheless, HSCT is rarely used because allogeneic transplantation is fraught with life-threatening complications. The highly efficient new gene editing technologies in combination with autologous HSCT may constitute a curative alternative for AT patients. Autologous HSCT circumvent the risk of graft versus host disease but the genotoxicity of conditioning regimens remains a significant obstacle to the implementation of this approach. Current conditioning approaches depend on irradiation or its combination with chemotherapy. These methods are particularly undesirable in AT patients that have a defective DNA repair system. Hence to fully realize the curative potential of HSCT in AT, the development of a non-genotoxic conditioning method that avoids undesirable toxicity is essential. Towards this goal, we propose to explore the use of internalizing immunotoxins that specifically target the HSC compartment to efficiently condition immunocompetent mice for HSCT. We will evaluate the toxicities associated with the use of immunotoxins and compare them with classic conditioning approaches. We will demonstrate disease correction in an Ataxia Telangiectasia mouse model using gene therapy corrected HSCs and immunotoxin based conditioning. Upon completion of the project, we expect to have in hand a novel immunotoxin ready for patenting, commercialization and/or clinical investigation.

4) To understand the Bone Marrow Microenvironment and its implication in Ageing, MDS and AML by integration of deep single-cell and spatial profiling.

Aging and age-associated morbidities, including cancer, are among the most important challenges facing western societies. Understanding aging and its relationship with cancer remains an unmet medical need. Stem cell niches, and in particular the hematopoietic stem cell niche present an opportunity to study physiology at the tissue level in aging and neoplasia. Here we leverage this opportunity to define the heterogeneity of the niche’s components and the changes associated with aging and neoplasia. While knowledge generated thus far has helped us envision the niche as a dynamic place, reductionist approaches describing single elements of a niche (mesenchyme) and their impact on stem cells (parenchyma) are reaching their boundaries. Hence, we propose an unbiased single-cell multi-omics-based integrative approach aimed at understanding: 1) cellular heterogeneity and cell-type specific gene regulatory networks that define the different cellular components of the hematopoietic niche; 2) the spatial arrangements of cells in the tissue and 3) how hematopoietic niche components, their regulation and spatial arrangements change during aging and neoplasia. This ground-breaking, multidisciplinary enterprise will provide the roadmap to define preventive and therapeutic strategies aimed at reducing age-associated morbidities, including cancer, adding quality of life and ultimately contributing to alleviating pressures on health and social systems in our society.