Dr. Yu Xin (Will) Wang received his PhD at the University of Ottawa where he identified cellular asymmetry and polarity mechanisms regulating muscle stem cell self-renewal and skeletal muscle regeneration. He then carried out postdoctoral training at Stanford University School of Medicine developing single cell multi-omic approaches to characterize the regenerative process and what goes awry with disease and aging.
“I’ve always had a passion for science and became fascinated with how the body repairs and heals itself when I was introduced to the potential of stem cells in regenerative medicine. I was struck by the ability of a small pool of muscle stem cells that can rebuild and restore the function of muscle. My lab at Sanford Burnham Prebys aims to better understanding the repair process and harness our body’s ability to heal in order to combat chronic diseases and even counteract aging.”
Education and Training
Postdoctoral Fellowship, Stanford University School of Medicine PhD in Cellular Molecular Medicine, University of Ottawa, Canada BS in Biomedical Sciences, University of Ottawa, Canada
Phenomena or Processes
Adult/Multipotent Stem Cells, Aging, Cell Signaling, Development and Differentiation, Epigenetics, Exercise, Extracellular Matrix, Neurogenesis, Organogenesis, Regenerative Biology, Transcriptional Regulation
Anatomical Systems and Sites
Immune System and Inflammation, Musculoskeletal System, Nervous System
Research Models
Clinical and Transitional Research, Computational Modeling, Human Adult/Somatic Stem Cells, Mouse
Techniques and Technologies
3D Image Analysis, Bioinformatics, Cellular and Molecular Imaging, Gene Knockout (Complete and Conditional), Genomics, High Content Imaging, High-Throughput/Robotic Screening, Live Cell Imaging, Machine Learning, Microscopy and Imaging, Proteomics, Transplantation
The Wang lab is interested in elucidating critical cell-cell interactions that mediate the function of tissue-specific stem cells during regeneration and disease, with a focus on
how a coordinated immune response can promote regeneration and
how autoimmunity impacts tissue function and hinder repair.
Specifically, the Wang lab aims to identify cellular and molecular crosstalk between muscle, nerve, and immune systems to develop targeted therapies that overcome autoimmune neuromuscular disorders and autoimmune aspects of “inflammaging.”
Yu Xin (Will) Wang’s Research Report
The lab’s research is translationally oriented and utilizes interdisciplinary molecular, genetic, computational (machine learning and neural networks), and bioengineering approaches to view biology and disease from new perspectives. We combine multi-omics sequencing and imaging methods to resolve how different cell types work together after injury to repair tissues and restore function. We use a data-driven approach to identify targetable disease mechanisms and, through collaborations with other researchers and clinicians, develop therapies that promote regeneration. Visit our lab website to learn more.
Pier Lorenzo Puri earned his MD at the University of Rome “la Sapienza” in 1991. Dr. Puri completed his internship in Internal Medicine at the hospital “Policlinico Umberto I” (Rome) from 1992 to 1997, and defended an experimental thesis on the vascular effects of angiotensin II to graduate as Specialist in Internal medicine at the University of Rome “la Sapienza” in 1997. During this time he was frequently working at the Freien University of Berlin, as visiting scientist at the Deprtment of Biochemistry and Molecular Biology, to perform experiments of protein and DNA microinjection in cultured cells. Dr. Puri trained as a post-doctoral fellow at the University of California San Diego (UCSD), in the department of Cell Biology, under the supervision of Dr. Wang, from 1997 to 2001. He was appointed as Staff Scientist at the Salk Institute (La Jolla) in 2001, and became an Assistant Telethon Scientist at the Dulbecco Telethon Institute in Rome in 2002. He was upgraded to Associate Telethon Scientist at the Dulbecco Telethon Institute in Rome since 2007 and became Senior Telethon Scientist, Dulbecco Telethon Institute, in 2012, but declined this position. Dr. Puri joined Sanford Burnham Prebys as an Assistant Professor in 2004. He has been promoted to Associate Professor in 2010 and full Professor in 2015. From 2008 to 2016 Dr. Puri served as Adjunct Professor of Pediatrics at the University of California, San Diego. From 2008 to 2013 Dr Puri was an Associate Member of Sanford Children’s Health Research Center. Dr Puri has been Director of the laboratory of Epigenetics and Regeneration at Fondazione S. Lucia, Roma, Italy, but stepped down this position since 2019.
Education
University of California San Diego, Postdoctoral, Department of Biology University of Rome La Sapienza, PhD, Internal Medicine University of Rome La Sapienza, MD, Internal Medicine University of Rome La Sapienza, Undergraduate, Internal Medicine
Other Appointments
2020-2024: Member of the Science Advisory Board (SAB) European Commission-funded Consortium BIND (Brain Involvement In Dystrophinopathies) 2015-2019: Standing Member, NIH Study Section (SMEP) 2010-present: Member of Editorial Board of Skeletal Muscle
Phenomena or Processes
Adult/Multipotent Stem Cells, Aging, Cell Biology, Cell Cycle Progression, Cell Differentiation, Cell Signaling, Cellular Senescence, Development and Differentiation, Disease Therapies, DNA Damage Checkpoint Function, Epigenetics, Gene Regulation, Phosphorylation, Regenerative Biology, Signal Transduction, Transcriptional Regulation
Anatomical Systems and Sites
General Cell Biology, Musculoskeletal System
Research Models
Clinical and Transitional Research, Cultured Cell Lines, Human Adult/Somatic Stem Cells, Mouse Embryonic Stem Cells, Mouse Somatic Stem Cells, Primary Human Cells
Techniques and Technologies
Bioinformatics, Cellular and Molecular Imaging, Gene Expression, Genomics
Puri’s lab group investigates the molecular and epigenetic regulation of gene expression in skeletal muscle progenitors and other muscle-resident cell types (including fibro-adipogenic progenitors, cells from the inflammatory infiltrate, cellular components of neuro-muscular junctions) during physiological and pathological perturbations of skeletal muscle homeostasis.
We use molecular, biochemical and epigenetic tools to understand structural and functional principles of the 3D genome organization that regulates gene expression during muscle regeneration and diseases.
A topic of particular interest is the analysis of chromatin interactions that define the 3D genome organization and the identification of structural and functional interactions that regulate cell type-specific patterns of gene expression in response to cues released within the skeletal muscle regenerative environment in health and disease conditions, such as muscular dystrophies and other neuromuscular diseases.
The knowledge derived from our studies is instrumental to elucidate the pathogenesis of muscular disorders and discover pharmacological interventions that promote muscle regeneration to repair diseased muscles.
Current translational focus is devoted to:
the study of the therapeutic potential of HDAC inhibitors for treatment of Duchenne Muscular Dystrophy (DMD)
the identification of genome variants associated to DMD patient-specific patterns of expression of disease-modifier genes that can account for individual trends of disease progression beyond the common genetic deficiency of dystrophin
the effect of dystrophin deficiency and restoration by gene therapy on 3D genome and transcriptional output of DMD myofibers; the therapeutic potential of extracellular vesicles released by fibro-adipogenic progenitors of DMD skeletal muscles exposed to HDACi.
Puri Lab
Pier Lorenzo Puri’s Research Report
Puri’s lab group investigates the molecular and epigenetic regulation of gene expression in skeletal muscle progenitors and other muscle-resident cell types (including fibro-adipogenic progenitors, cells from the inflammatory infiltrate, cellular components of neuro-muscular junctions) during physiological and pathological perturbations of skeletal muscle homeostasis.
We use molecular, biochemical and epigenetic tools to understand structural and functional principles of the 3D genome organization that regulates gene expression during muscle regeneration and diseases
A topic of particular interest is the analysis of chromatin interactions that define the 3D genome organization and the identification of structural and functional interactions that regulate cell type-specific patterns of gene expression in response to cues released within the skeletal muscle regenerative environment in health and disease conditions, such as muscular dystrophies and other neuromuscular diseases.
The knowledge derived from our studies is instrumental to elucidate the pathogenesis of muscular disorders and discover pharmacological interventions that promote muscle regeneration to repair diseased muscles
Current translational focus is devoted to:
the study of the therapeutic potential of HDAC inhibitors for treatment of Duchenne Muscular Dystrophy (DMD)
the identification of genome variants associated to DMD patient-specific patterns of expression of disease-modifier genes that can account for individual trends of disease progression beyond the common genetic deficiency of dystrophin
the effect of dystrophin deficiency and restoration by gene therapy on 3D genome and transcriptional output of DMD myofibers; the therapeutic potential of extracellular vesicles released by fibro-adipogenic progenitors of DMD skeletal muscles exposed to HDACi.
1. Epigenetic regulation of skeletal myogenesis by histone acetyltransferases and deacetylases
Our earlier identification and characterization of acetyltransferases p300/CBP and PCAF, as transcriptional co-activators, and the histone deacetylases HDACs, as transcriptional co-repressors, of the myogenic determination factor MyoD1-3, respectively, inspired the experimental rationale toward exploiting pharmacological inhibition of HDAC to promote skeletal myogenesis.
2. HDAC inhibitors as pharmacological intervention in DMD and other muscular dystrophies
Puri lab discovered that dystrophin-activated nNOS signalling controls HDAC2 activity, thereby revealing a previously unrecognized link between constitutive activation of HDAC2 and alteration of the epigenetic landscape of dystrophin-deficient muscles6,7. This discovery established the rationale for using HDAC inhibitors to counter the progression of Duchenne muscular dystrophy (DMD), by correcting aberrant HDAC activity in dystrophin-deficient muscles8-11.
3. Control of chromatin structure in muscle cells by regeneration-induced signaling pathways
Upon the discovery and characterization of intracellular signaling pathways (i.e. p38, ERK and AKT cascades) that regulate muscle gene expression in myoblasts, in earlier studies during Puri’s postdoctoral training, Puri lab has revealed the mechanism by which muscle environmental cues are converted into epigenetic changes that regulate gene expression in healthy and diseased muscles, via extracellular signal-activated kinase targeting of chromatin-modifying enzymes. These studies provided the first evidence that regeneration activated p38 and AKT signaling cooperatively direct assembly and activation of histone acetyltransferases and chromatin remodeling SWI/SNF complex at myogenic loci in muscle progenitors12,13,15. Moreover, we discovered that regeneration-activated p38 targets Polycomb Repressory Complex (PCR2) at Pax7 locus to promote formation of repressive chromatin during satellite cells a ctivation14.
4. Epigenetic basis for activation of the myogenic program in ESCs and other pluripotent cell types
Puri lab studied the epigenetic determinants of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) commitment to skeletal myogenesis, by investigating the hESC resistance to direct conversion into skeletal muscle upon ectopic expression of MyoD, which can otherwise reprogram somatic cells into the skeletal muscle lineage. These studies showed that hESC and hiPSC resistance to myogenic conversion is caused by the lack of expression of one structural component of the SWI/SNF chromatin remodelling complex – BAF60C – which is specifically induced in embryoid bodies13. Based on these studies, we have recently established a protocol of hESC-derived 3D contractile myospheres that offers the unprecedented opportunity to dissect and analyze the epigenetic dynamics that underlie the formation of skeletal muscles and to identify changes in the epigenome induced by contractile activity in healthy vs dystrophin-deficient myofibers16,20. We have also determined the identity of the general transcription factors implicated in the activation of skeletal myogenesis17, and we have discovered that replicative senescence is associated with acquisition of resistance to MYOD-mediated activation of muscle gene expression, caused by the constitutive activation of DNA damage repair (DDR) response that impairs cell cycle progression and MYOD activity18. Finally, our recent work has elucidated the mechanism by which MYOD regulates high-order chromatin interactions to define the tri-dimensional (3D) nuclear architecture for the activation of skeletal myogenesis during human somatic cell reprogramming into skeletal muscles19.
5. Identification, functional, phenotypic and molecular characterization of muscle-interstitial cells – (the fibroadipogenic progenitors – FAPs) in healthy and diseased muscles.
Our work has elucidated the molecular determinants of the interplay between adult muscle stem cells and cellular components of their functional niche (i.e. FAPs), by identifying regulatory networks implicated in compensatory or pathogenic regeneration, and suggesting “disease stage-specific” responses to pharmacological treatment of neuromuscular disorders, such as DMD. Indeed, we have shown that HDACi promote compensatory regeneration and prevent fibro-adipogenic degeneration in mdx mice at early stages of diseases, by targeting a population of muscle interstitial cells – FAPs8 – and have identified a HDAC-regulated network that controls expression of myomiRs and alternative incorporation of BAF60 variants into SWI/SNF complexes to direct the pro-myogenic or fibro-adipogenic FAP activity21. Furthermore, we have recently identified specific subpopulations of FAPs (subFAPs) in physiological conditions and disease22 and we have discovered that specific subFAPs expand and adopt pathogenic phenotypes upon muscle denervation23 or in muscles of patients affected by type 2 diabetes24.
After receiving his early training in clinical chemistry/biochemistry at the University of Buenos Aires, Argentina, Dr. Millán first joined the La Jolla Cancer Research Foundation (LJCRF) in 1977, the predecessor of Sanford Burnham Prebys, as a trainee in clinical enzymology. He completed his PhD studies in Medical Biochemistry at the University of Umeå, Sweden and after post-doctoral stints in Copenhagen and LJCRF he was appointed to the faculty at SBP in 1986. He served as Professor of Medical Genetics in the Department of Medical Biosciences at his alma mater, Umeå University, Sweden, from 1995-2000. He was appointed Sanford Investigator at the Sanford Children’s Health Research Center at Sanford Burnham Prebys in 2008.
Honors and Recognition
2018: ASBMR Lawrence G. Raisz Award for Pre-clinical Research. 2001: Gold Medal of the Royal Academy of Medicine and Surgery, Murcia, Spain 1992: Honorary title of AcadémicoCorresponsal at the Royal Academy of Medicine and Surgery, Murcia, Spain.
Related Disease
Arthritis, Bone Mineralization Disorders, Cardiovascular Diseases, Colorectal Cancer, Crohn’s Disease (Colitis), Heart Disease, Inherited Disorders, Metabolic Syndrome, Peripheral Vascular Disease, Testicular Cancer
Phenomena or Processes
Cardiovascular Biology, Disease Therapies, Extracellular Matrix, Protein Structure-Function Relationships
Anatomical Systems and Sites
Cardiovascular System, Musculoskeletal System, Vasculature
Research Models
Mouse
The Millán laboratory works on understanding the mechanisms that control normal skeletal and dental mineralization and elucidating the pathophysiological abnormalities that lead to heritable soft bones conditions such as Hypophosphatasia (HPP) and to soft-tissue calcification, including vascular calcification, that is a hallmark in patients affected by a variety of rare genetic diseases as well as in chronic kidney disease. Dr. Millán’s research has already contributed to the implementation of a novel therapy for HPP, a genetic disease caused by deficiency in tissue-nonspecific alkaline phosphatase (TNAP) function, that leads to accumulation in the extracellular space of inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. HPP is characterized by defective mineralization of bones (rickets or osteomalacia), and teeth that display a lack of acellular cementum, hypomineralized dentin and enamel, and periodontal defects. Dr. Millán’s team has demonstrated the effectiveness of enzyme replacement therapy using mineral-targeted recombinant TNAP (asfotase alfa) to prevent the skeletal and dental defects in the TNAP knockout mouse model of infantile HPP. This therapy was approved in 2015 for the treatment of patients with pediatric-onset HPP.
Current efforts, in collaboration with Professor Miyake’s group in Japan (https://www.nms-gt.org/en/members), focus on developing gene therapy as an alternative approach to treat HPP. Dr. Millán’s group has also identified key pathophysiological changes that lead to calcification of the arteries in animal models of generalized arterial calcification of infancy, pseudoxanthoma elasticum and related genetic diseases as well as in animal models of chronic kidney disease. His group, in collaboration with scientists at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys, has developed proprietary compounds able to ameliorate the soft-tissue calcification in these conditions and clinical trials are now underway using these first-in-class small molecule inhibitors.
