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Lung Inflammation & Repair

Prof. Dr. Ana Pardo-Saganta

Ana Pardo-Saganta is a professor at the Institute for Lung Health (ILH) of Justus Liebig University (JLU) in Giessen, Germany, where she leads the research group “Lung Inflammation and Repair”.

Ana Pardo-Saganta was born in Jaca, Huesca, Spain. After receiving her Bachelor degree (BSc) in Biology from the University of Navarra (Pamplona, Spain), she joined the Department of Gene Therapy and Hepatology at the Center for Applied Medical Research (Pamplona, Spain) to carry out her PhD (2003-2008). In 2009, she joined Dr. Jayaraj Ragagopal’s laboratory at the Center for Regenerative Medicine of Massachusetts General Hospital (MGH) (Boston, USA) as a postdoctoral fellow (2009-2014). In 2014, she received her first faculty position as an independent investigator at Harvard Medical School and the Division of Pulmonary and Critical Care at MGH (Boston, USA) and in 2016, she joined the Department of Regenerative Medicine of CIMA (Pamplona) after being awarded with the prestigious Ramón y Cajal Fellowship, to lead the group of “Stem cells and regeneration in lung disease”. Since then, she have obtained constant funding for her projects, she has been awarded by Fundación Astrazeneca (2021) as a recognition of her investigation in lung regeneration and respiratory disease, she has established multiple collaborations with top-notch experts in Europe and USA, she has published her findings in high profile journals (Nature, Cell Stem Cell) and contributed as an author to many other articles also published in top journals, and she direct 2 PhD thesis that sum up to her experience in teaching since she  worked as an assistant teacher of Genetics in the Faculty of Biology, Pharmacy and Medicine at the University of Navarra (2003-2007) and I have supervised six undergraduate students, one of them awarded with the Best Thesis Award from the Department of Stem Cell and Regenerative Biology (Harvard University). Additionally, she carries out an important task of dissemination of her research, also focused to make visible and support women in science.

The Pardo-Saganta lab seeks to identify the cellular and molecular mechanisms underlying lung inflammation, fibrosis and repair, focusing on the role of the complex intercellular communication between immune cells, epithelial (stem) cells and mesenchymal cells in the alveolar compartment of the adult lung in the pathogenesis, progression and resolution of disease. This knowledge will allow us to reach our major goal: to find efficient treatments for lung diseases that block the progression of the disease while promoting regeneration to recover functional tissue.

Our research investigates the interrelation between inflammation, fibrosis, regeneration and aging as relevant processes for lung homeostasis and pathogenesis. Given the complex interplay of these mechanisms and cell populations, we think that a unifying integration of all of these processes is required to understand higher order pathogenesis which can be compared to the physiology of the normal tissue. The Pardo-Saganta lab aims to understand the development of lung disease integrating cell interactions and the microenvironment at every step of injury progression: inflammation, fibrogenesis, resolution-repair.

Inflammation is the first response immediately triggered after injury and necessary to resolve damage. However, unresolved, uncontrolled or aberrant performance of inflammation contributes to the development of disease. Bacterial or viral infection that cause severe airway and alveolar injury, resulting in uncontrolled local and systemic inflammation, loss of alveolar barrier function and impairment of gas exchange, and the clinical manifestation of acute lung injury/ARDS. A tightly balanced, compartmentalized and spatially controlled immune response is therefore key to protecting the host from the invading pathogen without injuring the delicate alveolar architecture and jeopardizing the vitally mandatory level of gas exchange function.

The lung epithelium is one of the major pathogen sensors and orchestrators of the initial immune response of the entire body. It elicits a multitude of cell-autonomous stress responses to cope with the invading pathogen and induces an inflammatory response by instructing circulating and tissue-resident immune cells to fight invading pathogens. This might result in rapid pathogen clearance and maintenance of parenchymal integrity at best, or in extensive tissue destruction with non-contained, systemic inflammation at worst. In fact, the epithelial surveillance mechanisms and cellular communication networks involved in the timely fine-tuning and balancing of these responses need to be tightly adjusted to the requirements of the infected and injured bronchoalveolar compartment. The mechanisms controlling this delicate balance remains unknown.

We have recently discovered a cellular interaction between airway stem cells and tissue resident immune cells that is essential to maintain these antigen-presenting cells at homeostasis and that the disruption of their cellular communication impedes the initiation of an immune response. This type of intercellular communication may occur in every region of the respiratory tree in many different pathological conditions and may be a key mechanistic link between stem cell exhaustion and impaired immune response in lung disease. Thus, understanding the key role of stem cells in the regulation of the immune response will help to develop immune-mediated mechanisms of regeneration and repair that may complement existing stem cell therapies to promote functional regrowth of vital tissues.

Contrary to acute lung injury, chronic lung disease develops over extended periods of time most likely on a scenario/context of low-grade inflammation developed during aging that may predispose the tissue and contribute to the pathogenesis of age-related diseases such as IPF or COPD. In addition to dysfunctional inflammatory cells, chronic lung diseases are also characterized for failure in mechanisms of repair. In the last years, novel epithelial progenitor cells have been identified and demonstrated to contribute to lung repair. Recent findings shed light to the mechanisms of regeneration of the bronchioalveolar epithelium; however, a better understanding of the coordinated processes of tissue repair from different stem cell pools after injury is crucial to restore the delicate lung architecture. The contribution of the interplay between these epithelial progenitor populations and other cell types of their niche to the development of disease, needs further investigation (Figure 1).

Figure 1. Overview of the cellular interplay addressed by the Pardo-Saganta lab

Deciphering the key cellular and molecular events balancing effective host defense and beneficial epithelial stress responses versus parenchymal damage, overshooting inflammation and aberrant repair will provide novel targets of intervention to drive injury resolution and tissue repair while maintaining functional anti-bacterial and anti-viral host defense.

Accordingly, the professorship for Lung Inflammation and Repair aims to achieve the following objectives:

  1. To investigate how epithelial stem cells maintain a functional immune ecosystem Including the implication of epithelial stem cells in regulating the lung host competence. And the role of this functional immune-ecosystem in bacterial and viral pathogen-induced lung injury.
  2. To understand the effect of a persistent inflammatory context to the development of lung disease studying the role of clonal hematopoiesis of indeterminate potential (CHIP; based on various hematopoietic stem cell mutations) in the development of respiratory diseases.
  3. To examine the therapeutic potential of targeting Notch3 signaling to treat pulmonary fibrosis. We have also identified the source of the Notch ligands presumably activating Notch3 in neighboring fibroblasts to induce their differentiation into myofibroblasts. Thus, Notch3-mediated epithelial cell-fibroblast communication emerges now as a potential therapeutic target for the treatment of pulmonary fibrosis.
  4. To unravel Notch3-based mechanisms involved in pulmonary hypertension (PH). We will study the cellular communication between endothelial cells presumably providing Notch ligand to vascular smooth muscle cells to activate Notch3 and enhance PH phenotype.
  5. To characterize and explore the regenerative potential of newly identified epithelial cells.

 

Contact

Email: apardosa@unav.es

 

 

Ten most important publications

  1. Vera L., Garcia-Olloqui, P., Petri E., Viñado A.C., Valera P.S., Blasco-Iturri Z., Calvo I.A, Cenzano I., Ruppert C., Zulueta J.J, Prosper F., Saez B, Pardo-Saganta A. Notch3 deficiency attenuates pulmonary fibrosis and impedes lung function decline. Am J Respir Cell Mol Biol 2021, 64(4):465-476. IF: 6.9
  2. Causton B, Pardo-Saganta A, Gillis J, Discipio K, Kooistra T, Rajagopal J, Xavier RJ, Cho JL, Medoff BD. CARMA3 Mediates Allergic Lung Inflammation in Response to Alternaria alternata. Am J Respir Cell Mol Biol. 2018, 59(6):684-694. IF: 6.9
  3. Pardo-Saganta A, Tata PR, Law BM, Saez B, Chow RDz, Prabhu M., Gridley, T, Rajagopal J. Parent stem cells can serve as niches for their daughter cells. Nature 2015, 523(7562): 597-601. IF: 42.77
  4. Causton B, Ramadas RA, Cho JL, Jones K, Pardo-Saganta A, Rajagopal J, Xavier RJ, Medoff BD. CARMA3 is critical for the initiation of allergic airway inflammation. J Immunol. 2015 Jul 15;195(2):683-94. IF: 5.42
  5. Pardo-Saganta A, Law B, Tata PR, Villoria J, Saez B, Mou H, Zhao R, Rajagopal J. Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations. Cell Stem Cell 2015, 16(2):184-197. IF: 20.86
  6. Yu VWC, Saez B, Cook C, Lotinun S, Pardo-Saganta A, Wang YH, Lymperi S, Raaijmakers MH, Wu JY, Zhou L, Rajagopal J, Kronenberg HM, Baron R, Scadden DT. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med. 2015 May 4;212(5):759-74. IF: 11.74
  7. Saez B, Ferraro F, Yusuf RZ, Cook CM, Yu VW, Pardo-Saganta A, Sykes SM, Palchaudhuri R, Schajnovitz A, Lotinun S, Lymperi S, Mendez-Ferrer S, Del Toro R, Day R, Vasic R, Acharya SS, Baron R, Lin CP, Yamaguchi Y, Wagers AJ, Scadden DT. Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood 2014, 124(19): 2937-2947. IF: 17.54
  8. Zhao R, Fallon TR, Saladi SV, Pardo-Saganta A, Villoria J, Mou H, Vinarsky V, Gonzalez-Celeiro M, Nunna N, Hariri LP, Camargo F, Ellisen LW, Rajagopal J. Yap tunes airway epithelial size and architecture by regulating the identity, maintenance, and self-renewal of stem cells. Dev Cell. 2014 30 (2):151-165. IF: 10.09
  9. Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M, Law BM, Vinarsky V, Cho JL, Breton S, Sahay A, Medoff BD, Rajagopal J. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 2013, 503 (7475): 218-223. IF: 42.77
  10. Pardo-Saganta A, Law BM, Gonzalez-Celeiro M, Vinarsky V, Rajagopal J. Ciliated cells of pseudostratified airway epithelium do not become mucous cells after OVA challenge. Am J Respir Cell Mol Biol. 2013, 48(3): 364-373. IF: 6.9

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