Translational and Regenerative Medicine Group - Maria Paola Santini
Maria Paola Santini, PI, Tenure-Track Assistant Professor, Adjunct Assistant Professor at Icahn School of Medicine at Mount Sinai, NY, NY, USA
Email: mariapaola.santini@unipv.it
Tel: +39 0382987784
Raima Remesh, PhD student
Our laboratory investigates the mechanisms and therapeutic approaches for inhibiting
multiorgan fibrosis in ischemic diseases and aging and eliciting tissue revascularization
and organ integrity. Special emphasis will be devoted to the cardiovascular system,
kidney and skeletal muscle.
i) Skeletal muscle
Supported by the Leducq Foundation, we discovered that PDGFR-mesenchymal stromal cells have a ‘yin-yang’ dual function, in which they may induce relevant aging-like processes but also promote therapeutic control of the pathological mechanisms leading to senescence. We observed that the regenerative efficiency of young PDGFRα cells is associated to regulation of transcripts involved in resolution of inflammation and increased mesodermal and proliferative signaling.
Based on these data, we are investigating the genomic and functional relevance of this signaling during aging using transgenic technologies and multi-omic network analyses. We are further testing the therapeutic control of muscle regeneration and rejuvenation by adoptive transfer of young PDGFRα+ stromal compartment to senescent or diseased (DMD) muscles.
Similarly, we are exploring the possibility of cross-organ PDGFRα+ stromal replacement from skeletal muscle to non-regenerating cardiac muscle.
ii) Cardiovascular system
Supported by the American Heart Association and NIH/NHBLI we have discovered novel features of cardiac PDGFRα biology, which challenge the prevailing notions on its signaling, localization and cellular heterogeneity. Briefly, we observed that (1) PDGFRα is not a unique marker of fibroblasts but it is expressed in several cardiac populations, indicating that the heart contains an extended cellular domain associated with PDGFRα expression; (2) nuclear shuttling of the catalytic PDGFRα tyrosine kinase domain (TKD) is present in cardiomyocytes and to a lower extend in fibroblasts in response to ischemia, suggesting that spatiotemporal control of PDGFRα define the functional ‘status’ rather than the type of cardiac cells in response to an injury; (3) modulation of the paracrine environment using gene therapy to overexpress isoforms of IGF-1 showed increased regenerative potential of the PDGFRα domain in tissue revascularization. Based on these data, we will define the spatiotemporal regenerative functions of specific cardiac PDGFRα cells using novel orthogonal transgenic technologies Dre/Cre-Rox/Lox and spatial transcriptomic and will identify the biological significance of PDGFRα TKD nuclear localization signaling using systems biology and mutagenesis analyses. Further analyses on IGF-1 gene therapeutic relevance will be developed to test mutants with stringent local expression to avoid off-target effects.
iii) Kidney
Supported by the American Heart Association, we have discovered a gender-specific resistance to chemotherapy -induced nephrotoxicity modulated by trans-differentiation of PDGFRα cells into endothelial cells and podocytes. To understand these mechanisms, we will uncover the function of renal PDGFRα cells using integrated network analyses in transgenic mice with conditionally regulated PDGFRα cellular domain during chemotherapy regimen, and characterize the human 3D spatial transcriptomic profile of renal PDGFRα cells in response to chemotherapy using human iPSC-derived organoids.