Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration published

Congratulations to Ermelinda and the rest of the Blau, Fantl, and Jackson lab authors on their recent publication in Cell Stem Cell. Their manuscript, which which is the current cover article,  highlights a previously unrecognized age-dependent alteration in CD47 levels and function in muscle stem cells (MuSCs), which underlies reduced muscle repair in aging. Capitalize on mass cytometry, the authors identified high CD47 expression as a hallmark of dysfunctional MuSCs with impaired regenerative capacity that predominate with aging. This dysfunctional CD47hi MuSC subset, which arises via altered poolyadenylation triggered by an age-associated increase in U1 expression, suppresses the residual functional CD47lo MuSC subset through a paracrine signaling loop, leading to impaired proliferation. Importantly, the deficit in aged MuSC function in regeneration can be overcome either by morpholino-mediated blockade of CD47 alternative polyadenylation or antibody blockade of thrombospondin-1/CD47 signaling, leading to improved regeneration. More details available in this article from Stanford Medicine.

Asuka Eguchi speaks at CVI Early Career Symposium

Blau lab Instructor Asuka Eguchi, PhD, presented her work in a lightening talk entitled Toward Safer Gene Therapy Strategies for Duchenne Muscular Dystrophy at the Stanford Cardiovascular Institute's 2022 Early Career Symposium. The event took place on October 17, 2022 and featured talks by Stanford postdoctoral fellows, staff scientists, Instructors, and faculty. Sessions included Career Development, Biomechanics, Basic Science, Translational Medicine, and Lightening Talks.

Plasticity of muscle stem cells in homeostasis and aging published

We are living longer, but our healthspan has not increased. The goal of regenerative medicine is to increase quality of life through an understanding of the cellular and molecular processes that underlie effective tissue repair in order to restore damaged tissues. The drivers of muscle regeneration are the muscle stem cells that cycle between quiescent and activated states to meet tissue regenerative demands. Here we review recent findings on the role of the niche, or tissue microenvironment, in the modulation of muscle stem cell plasticity and the mechanisms responsible for the drastic loss of stem cell function with aging. These new studies unveil fundamental mechanisms of stem cell plasticity with broad relevance to other tissues and lay the foundation for the development of therapeutic strategies to boost the regenerative potential of aged muscle stem cells

Blau lab hosts M&I “Regenerating Happy Hour" 

The Blau lab will host the weekly M&I happy hour on Friday, October 7th from 4-6pm on Discovery Walk. The Blau lab will be serving special elixirs, classic drinks and snacks! Thanks to Dan and Elena for organizing.

Helen Blau Speaks at CVI Frontiers in Cardiovascular Science Seminar Series

She delivered an hour long seminar Regenerating and Rejuvenating Aged Muscles by Targeting a “Gerozyme” to a packed room on September 13, 2022. The talk focused on the Blau’s lab discovery that elevated 15-PGDH, the Prostaglandin E2 degrading enzyme, is a hallmark of aged muscle and other tissues. 15-PGDH overexpression triggers atrophy in young muscles, whereas its inhibition rejuvenates and strengthens aged muscles. The potency of PGE2, which accumulates following 15-PGDH inhibition, arises from its dual targets: muscle stem cells and mature myofibers. These findings hold promise for translation to the clinic to augment strength in patients with muscular dystrophies and sarcopenia, the debilitating loss of muscle function with aging for which there currently is no treatment.

Frontiers in Cardiovascular Science hybrid seminars are every Tuesday from 12 PM – 1 PM PT. 

Adriana, Aarushi, and Asuka present their data at the 2022 BioX Summer Poster Session

High School intern Aarushi, undergraduate Adriana, and postdoc mentor Asuka each presented their data on August 26, 2022 a part of the BioX Summer Research poster session. Their poster titles were:

  • Aarushi - Mapping the function of neuromuscular junction in health and disease
  • Adriana - Promoter Designs for Gene Therapy of Muscle Disorders
  • Asuka - Design of Gene Therapy Strategies for Duchenne Muscular Dystrophy

Leahlyn Mamuyac presents at the Stanford CVI 2022 Summer Research Symposium

Leahlyn presented data gathered as a part of her summer research experience in the Blau lab working with Asuka Eguchi, PhD.  Leahlyn's talk was entitled Microdystrophin gene therapy for Duchenne Muscular Dystrophy cardiomyocytes and it provided insights into her data comparing the ability of three dystrophin variants that are currently in clinical trials to rescue DMD-associated pathological phenotypes in cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs).  The event program, including Leahlyn's abstract, is available here.

Ian Stancil awarded T32 from the Buck Institute

Blau lab postdoctoral fellow Ian Stancil was awarded a spot on the Buck Institute's prestigious T32 Training in basic research on aging and age-related disease  fellowship training programThis training program provides postdoctoral fellows with advanced research training in modern disciplines, including functional genomics, epigenomics, proteomics, molecular biology, cell biology, bioenergetics, chemical screening, microanatomy and powerful cellular and animal models.

Dan Robinson and Minas Nalbandian awarded travel fellowships

Blau lab postdoctoral fellows Dan Robinson and Minas Nalbandian were each awarded a travel fellowship to present their data at the 2022 FASEB Myogenesis meeting.  Dan's award was sponsored by FASEB, while Minas received support from the Stanford Cardiovascular Institute's Travel Grant program

Blau lab, past and present, meet at the 2022 FASEB Skeletal Muscle Stem Cells and Regeneration Conference in New Orleans

Current and past members of the Blau lab met to discuss their work and reconnect at the FASEB Myogenesis meeting held July 24-29, 2022 in New Orleans.  The conference aims to accelerate the translation of fundamental advances into novel clinical treatments through the interactions of basic and clinical researchers. It provides opportunities for interaction and mentoring between junior scientists and senior investigators to foster career development. Helen presented the closing keynote, while Faye, Fabio, and Penney presented in specialized sections. Ermelinda, Dan, and Minas presented posters on their projects.

Asuka Eguchi awarded a Career Development Grant from the Muscular Dystrophy Association

Asuka Eguchi was awarded a prestigious Development Grant from the MDA for her proposal Microdystrophin Design for the Treatment of Dystrophin-Deficient Cardiomyocytes. Duchenne muscular dystrophy (DMD) affects 1 out of 3,500 males. DMD patients exhibit severe muscle degeneration and die of respiratory or heart failure. The project's goal is to distinguish the most effective gene therapy for the heart by comparing how well the different versions of microdystrophins being tested in clinical trials along with minidystrophin identified in a Becker patient with mild dystrophic symptoms rescue disease phenotypes exhibited by DMD cardiomyocytes differentiated from human induced pluripotent stem cells (iPSC-CMs).

Will Wang speaks in the Myogenesis Discussion group sponsored by Medicine by Design at the University of Toronto

The study of myology (skeletal, smooth and cardiac muscle structure, function and development) has wide-ranging importance in the field of regenerative medicine. Skeletal muscle is the most abundant tissue in the human body and cardiac muscle is required to circulate blood throughout it. Furthermore, smooth muscle is present in the walls of hollow organs and the vasculature system, making these tissues critical for normal physiological function. The goal of this discussion group is to explore models of development, disease and regeneration in muscle tissues, as well as potential therapeutic approaches. Within this, we aim to discuss novel techniques to quantitatively measure all aspects of myology and the challenges associated with developing representative models for these complex tissues. Will's talk is entitled A Single Cell Spatial Temporal Atlas of Skeletal Muscle Reveals Cellular Neighborhoods that Orchestrate Regeneration and Become Distrupted in Aging.

Helen Blau Co-Organizes 2022 Pontifical Academy of Sciences Stem Cell Meeting

Two major types of stem cells exist during the lifecycle of multicellular organisms: embryonic stem cells, resulting from the early divisions of the egg, characterized by their “pluripotency”, i.e. the capacity, that they share with the egg cell itself, to produce all the cell types found in the adult organism, and the tissue-specific stem cells present in the tissues and organs of the adult. The latter play an important role in renewing the cells of the various organs during the entire life. Top stem cell biologists met at this workshop to discuss the pressing questions of the field. The final statement from the meeting is available here.

Helen Blau presents in 2021-2022 TRAM Lecture series

The Translational Research and Applied Medicine (TRAM) Center is designed to focus on removing barriers and communication gaps between scientists and the clinicians. Helen Blau spoke to the program participants about the lab's recent research into 15-PGDH and its role rejuvenating aged muscle on March 30, 2022.

TRAM has provided Pilot Grant support to many Blau lab members, most recently Asuka Eguchi, PhD, (2020-2022 TRAM Scholar) and Will Wang , PhD (2017-2018 TRAM Scholar).

"Primary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging" published in Nature Communications

In this collaboration between the Blau and Jackson labs, lead authors Adelaida R. Palla and Keren I. Hilgendorf show that the ability of muscle stem cells to regenerate is regulated by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Their findings provide fresh insights into signaling dysfunction exhibited by aged muscle stem cells and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging.

"Tamoxifen treatment ameliorates contractile dysfunction of Duchenne muscular dystrophy stem cell-derived cardiomyocytes on bioengineered substrates" published in Nature Regenerative Medicine

Duchenne muscular dystrophy (DMD) is a progressive genetic myopathy that leads to heart failure from dilated cardiomyopathy by early adulthood. In this publication lead authors Foster Birnbaum and Asuka Eguchi applied a unique bioengineered human-induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to shed light on how tamoxifen, a selective estrogen receptor modulator widely used to treat breast cancer, could be applied to treat DMD cardiomyopathy. Their data show that 4-hydroxytamoxifen treatment of DMD iPSC-CMs decreased beating rate, increased beating velocity, and ameliorated calcium-handling deficits, leading to prolonged viability.

Also featured in a CVI article by Adrienne Mueller, PhD!

Helen Blau Elected to the ISSCR Board of Directors

With nearly 4,000 members from more than 65 countries, the International Society for Stem Cell Research is the preeminent global, cross-disciplinary, science-based organization dedicated to stem cell research and its translation to the clinic. The ISSCR mission is to promote excellence in stem cell science and applications to human health. The following two scientists were newly elected to the ISSCR Board of Directors for a three-year term:

Elena Monti and Dan Robinson Join the Blau Lab

The Blau lab is excited to have new postdoctoral fellows Elena Monti, PhD, and Dan Robinson, PhD join the lab. Welcome!

Blau Lab Awarded an Inaugural Milky Way Research Foundation Grant

There are currently no treatments for sarcopenia, a debilitating aging-associated loss of muscle function. The Blau lab recently published in Science that decreasing the abundance of Prostaglandin E2 (PGE2) triggers premature muscle aging in young mice, and increasing its levels rejuvenates muscles of aged mice. This physiologic shift in PGE2 concentration is mediated by 15-PGDH, the enzyme that degrades PGE2, which appears to be a pivotal molecular determinant of muscle aging. In mice and humans, 15-PGDH expression increases with age. Even brief systemic 15-PGDH inhibition not only augments muscle mass and strength, but also increases time to exhaustion on a treadmill, suggests a more general amelioration of aged tissue function. The proposed project explores the hypothesis that 15-PGDH is a “master regulator of aging” and its inhibition restores PGE2 homeostasis and leads to organismal rejuvenation, augmenting healthspan and lifespan.

Mohsen Afshar Awarded Dean's Fellowship

Postdoctoral Fellow Mohsen Afshar was awarded a Stanford School of Medicine Dean's Postdoctoral Fellowship for his project Role of 15-PGDH in neuromuscular junction aging and rejuvenation.

Reversing Aging for Heart Repair published in Science

A Regenerative Medicine Perspective written by Will Wang and Helen Blau published in the September 23 issue of Science.

Chris Madl speaks at M&I weekly Seminar Series

Postdoctoral Fellow Christopher Madl presents his research talk Dynamic engineered microenvironments to deconvolve outside-in signaling in the muscle stem cell niche as part of the Department of Microbiology and Immunology's weekly seminar series.

Mohsen Afshar awarded SUMS Seed Grant

Postdoctoral fellow Mohsen Afshar was awarded a SUMS Seed Grant for his proposal Quantifying cellular NAD+ metabolome using a liquid chromatography coupled to mass spectrometry approach. NAD+ is known to be a key regulator of metabolism and longevity. Aging is accompanied by changes in NAD+ metabolome. The Blau Lab has recently identified a novel target, 15-PGDH, that acts as a master regulator of muscle rejuvenation in aged mice by restoring mitochondrial activity. This proposal allows development of a novel method to measure key components of NAD+ metabolome in aged mouse muscles post 15-PGDH inhibition.

Congratulations to Christopher Madl on his K99 Award 

His proposal, Elucidating Effects of Fibrosis on Aged Stem Cells with Dynamic Biomaterials,  aims to develop a dynamic material platform that enables user-directed manipulation of stiffness and to apply this system to identify aging-related changes in muscle stem cells that could lead to novel therapies to improve muscle function.

Biophysical matrix cues from the regenerating niche direct muscle stem cell fate in engineered microenvironments published in Biomaterials.

Madl CM, Flaig IA, Holbrook CA, Wang YX, Blau HM.Biomaterials. 2021 Jun 14;275:120973. doi: 10.1016/j.biomaterials.2021.120973. Online ahead of print.PMID: 34224984.

Markov et al. published in PNAS

AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency.

Markov GJ, Mai T, Nair S, Shcherbina A, Wang YX, Burns DM, Kundaje A, Blau HM.Proc Natl Acad Sci U S A. 2021 Jun 8;118(23):e2104841118. doi: 10.1073/pnas.2104841118.PMID: 34088849

Sofía Isabel Torres Bigio Joins as a Summer Intern 

Sofia is a rising Senior at MIT majoring in molecular Biology and Computer Science. She arrives as a part of the Stanford Cardiovascular Institute's Summer Research Program. Welcome to the lab Sofia!

Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes published in Stem Cell Reports

Alex C Y Chang, Gaspard Pardon, Andrew C H Chang, Haodi Wu, Sang-Ging Ong, Asuka Eguchi, Sara Ancel, Colin Holbrook, John Ramunas, Alexandre J S Ribeiro, Edward L LaGory, Honghui Wang, Kassie Koleckar, Amato Giaccia, David L Mack, Martin K Childers, Chris Denning, John W Day, Joseph C Wu, Beth L Pruitt, Helen M Blau. Stem Cell Reports. 2021. May 11;S2213-6711(21)00213-7. doi: 10.1016/j.stemcr.2021.04.018. 

Shiqi Su Joins the Blau Lab

University of California Irvine graduate Shiqi Su joined the Blau lab as a technician in May 2021. Previously Shiqi was an undergraduate researcher in the Piomelli Lab

Will Wang speaks in Spatial Multiomics Webinar Series: Enriching Spatial Proteomic Data with Parallel CITE-seq Analysis Elucidates Multiomic Changes with Aging

Integrating complementary data sets provides a powerful tool to study complex biological processes. In this webinar, Dr. Will Wang from Stanford University will discuss the use of CODEX (Co-Detection by Indexing) spatial proteomic data in parallel with CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) data to study tissue regeneration and aging. In this talk, attendees will learn about the use of multiplex imaging to study spatial dynamics of skeletal muscle regeneration and molecular determinants of aging, understand how to design and align CITE-seq experiments to enrich CODEX data, and see how to use single-cell resolution spatial transcriptomes to assess cell-cell signaling.

Blau lab welcomes new postdoctoral fellow Mohsen Afshar

Mohsen Afshar joined the Blau lab in March 2021. Mohsen completed his PhD studies with Blau lab alum Penney Gilbert in her lab at the University of Toronto studying various aspects of skeletal muscle regeneration and related signalling pathways. 

Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength published in Science

AR Palla, M Ravichandran, YX Wang, L Alexandrova, AV Yang, P Kraft, CA Holbrook, CM Schürch, ATV Ho, HM Blau. Science. 2021 Jan 29;371(6528):eabc8059. doi: 10.1126/science.abc8059. PMID: 33303683 PMCID: PMC7938328. 

Helen Blau and Sarah Heilshorn awarded 2020 Keck Foundation Medical Research Award

Helen Blau and Sarah Heilshorn were jointly awarded a 2020 Keck Foundation Medical Research Award for their proposal Dynamic Biomaterials to Probe the Role of Tissue Stiffening in Proliferation-Independent Telomere Dysfunction. The Blau lab recently identified telomere shortening as a hallmark of DMD cardiomyopathy, as well as of other heritable cardiomyopathies, leading the investigators to postulate that telomere shortening plays a causal role in heart failure in many genetic diseases. However, this hypothesis is controversial, given that telomere shortening has historically been associated with cell division, and cardiomyocytes do not divide. The investigators will determine whether mechanical stress drives telomere shortening and subsequent pathogenic signaling, leading to cardiomyocyte death. They have developed a novel hydrogel platform that can be stiffened and softened on demand to tune mechanical load, which will be used in conjunction with human induced pluripotent stem cell derived cardiomyocytes from DMD patients and live cell imaging to answer the fundamental question: How can telomeres shorten without cell division? 2021 CVI Winter Quarterly, pg 17.

Will Wang awarded K99/R00 Pathway to Independence Award

Congratulations to Blau postdoctoral fellow Yu Xin "Will" Wang on being awarded a K99/R00 Pathway to Independence Award from the National Institute of Neurological Disorders and Stroke for his proposal Spatial Regulators of Skeletal Muscle Regeneration and Disease

Blau lab receives grant from the Spinal Muscular Atrophy Foundation and the Stanford Innovative Medicines Accelerator

Gene therapy has shown remarkable promise for the successful treatment of the root cause of spinal muscular atrophy (SMA). However, combined therapeutic approaches that treat all aspects of SMA, including regenerating muscle, are still urgently needed. In this project, jointly funded by the SMA Foundation and the Stanford IMA, the Blau lab will test their hypothesis that 15-PGDH inhibition will synergize with an available therapy that restores SMN expression to increase neuromuscular junctions and improve muscle function.

Congratulations to Meenakshi Ravichandran on her SNSF Fellowship

Postdoctoral Fellow Meenakshi Ravichandran was awarded a Postdoc.Mobility Fellowship from the Swiss National Science Foudnation. Her research project proposes to test if boosting PGE2 levels can stimulate muscle growth in the diaphragm.