Black Family Stem Cell Institute

Stem Cell Microenvironment

Each day, adult humans generate billions of new cells to replace those that are lost naturally or by damage in organ systems, such as the blood, muscle, skin, intestine, and brain.

At the top of the production hierarchies are the stem cells that can make all the different cell types in each tissue and can self-renew. While stem cells have many built-in controls, they rely for proper function on outside signals from their immediate environment, also called stem cell microenvironment or niche. Also, cancer stem cells are influenced by their environment, which they exploit to boost cancer growth.

We must understand how the niche regulates the regenerative functions of stem cells, which goes awry in cancers, to unlock the potential of stem cells in diseased, injured, or aged tissues for therapeutic regeneration; generate cells from pluripotent or tissue stem cells in the laboratory for transplantation and drug testing; and deprive cancer stem cells of their growth advantage in novel anticancer therapies. Several laboratories at the Black Family Stem Cell Institute are working toward meeting these goals.

Investigators with a major focus in the stem cell environment include:

Julio Aguirre-Ghiso

Julio Aguirre-Ghiso, PhD, is a Professor at the Icahn School of Medicine at Mount Sinai in the Division of Hematology and Oncology in the Departments of Medicine, Otolaryngology, and Oncological Sciences; the Research Leader of the Metastasis Treatment Center and Co-leader of the Cancer Mechanisms Program at The Tisch Cancer Institute, an NCI-designated center, and Director of Head and Neck Cancer Basic Research in the Department of Otolaryngology. He focuses on one of the major challenges faced by physicians: prevention and treatment of metastasis, which is the main reason for cancer mortality. Cancer patients presumed cured after primary tumor removal and therapy can carry non-proliferating ‘dormant’ disseminated tumor cells (DTCs) for years before reactivating to form incurable metastasis. Dr. Aguirre-Ghiso’s work focuses on understanding the biology of residual cancer cells that persist in a dormant state after initial therapy. His team led a paradigm shift revealing novel cancer biology that diverges from the notion that cancer is perpetually proliferating. They discovered that reciprocal crosstalk between DTCs and the microenvironment regulates the inter-conversion between dormancy and proliferation. This knowledge will allow targeting minimal residual disease before it becomes clinically detectable, and thus preventing recurrences.

Ongoing research interests include:

  • Exploring mechanisms controlling residual cancer dormancy
  • Researching approaches to target dormant cancer cells
  • Identifying markers to determine whether disseminated disease cells are dormant or active

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Margaret H. Baron, MD, PhD

Margaret H. Baron, MD, PhD, is the Irene and Arthur M. Fishberg Professor of Medicine and Professor of Cell, Developmental and Regenerative Biology, and Oncological Sciences at the Icahn School of Medicine at Mount Sinai. She is also Senior Associate Dean for MD/PhD Education and Director of the Medical Scientist Training Program (MSTP, MD/PhD programs). Her laboratory's research focuses on basic mechanisms in mammalian blood cell (hematopoietic) development. Researchers used transgenic mouse reporter lines to image, purify, and generate transcriptomes from the earliest (primitive) blood progenitors and their descendants and showed that the canonical Wnt/b-catenin signaling pathway plays a role in regulation of the emergence and maturation of primitive erythroid (red blood cell, RBC) progenitors. In contrast, the vitamin D receptor (VDR) nuclear hormone transcription factor gene is expressed in fetal and adult but not embryonic erythroid progenitors and is downregulated during maturation. Activation of VDR signaling by its ligand vitamin D stimulates the growth of erythroid progenitors, resulting in a large increase in the numbers of mature RBCs. Activation of VDR can partially substitute for and synergize with the stress glucocorticoid dexamethasone to enhance progenitor proliferation, suggesting a role in stress erythropoiesis.

Dr. Baron is also conducting RNA-seq analysis to identify signaling pathways and regulators that function downstream of VDR signaling. Such studies have the potential to identify new therapeutic targets for treatment of anemias and other blood disorders.

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Nicole C. Dubois, PhD

Nicole Dubois, PhD, received her PhD in Cell and Developmental Biology from the Swiss Institute for Experimental Cancer Research and the University of Lausanne with Andreas Trumpp, PhD. She did her postdoctoral training in the laboratory of Gordon Keller, PhD, at the University Health Network in Toronto with a focus on pluripotent stem cell biology and their differentiation to cardiovascular lineages. She is currently an Associate Professor in the Department of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai, the Black Family Stem Cell Institute, and the Mindich Child Health and Development Institute. Dr. Dubois' group studies early heart development and congenital heart disease using pluripotent stem cell differentiations and the mouse embryo as model systems.

Ongoing research interests include:

  • Understanding the molecular mechanisms of atrial-ventricular development
  • Exploring pluripotent stem cell differentiation to cardiovascular lineages
  • Looking at cardiac maturation and tissue engineering
  • Investigating long non-coding RNAs during cardiac development
  • Exploring cardiac toxicity of cancer drugs (LINCS project)

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Elena Ezhkova, PhD

Elena Ezhkova, PhD, is an Associate Professor in the Cell, Developmental, and Regenerative Biology Department. Her laboratory implements an array of powerful cellular and high-throughput molecular biology tools to dissect how epigenetic gene regulators, specifically the polycomb repressive complexes 1 and 2 (PRC1 and PRC2), play a role in cell fate determination, homeostasis, and regeneration. Her lab has recently showed that PRC1 functions both as a transcriptional repressor and as a transcriptional activator during skin development. Importantly, PRC1-mediated gene activating functions are critical for hair follicle development and for the establishment of the adult bulge stem cell compartment. Identification of these molecular mechanisms that control cell fate determination, commitment, and differentiation aids in expanding our understanding of tissue development and the progression of various tissue disorders, including cancer. 

Ongoing research interests include:

  • Uncovering the molecular mechanism of PRC-mediated gene regulation in skin development, homeostasis, and regeneration
  • Dissecting the canonical and non-canonical PRC function in different epithelial tissues, including skin and oral epithelia
  • Uncovering the molecular mechanisms controlling Merkel cell development and maintenance and Merkel cell carcinoma formation

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Saghi Ghaffari, MD, PhD, is a Professor of Cell, Developmental, and Regenerative Biology and a member of The Tisch Cancer Institute. Her lab studies mechanisms that sustain blood forming stem and progenitor cells (HSPCs) throughout life and that are perturbed in disease. Her team is particularly interested in programs that maintain quiescence of blood-forming stem cells, a property that determines the potency and overall regenerative capacity of adult stem cells and that is lost with age. Quiescence is also a mechanism by which malignant stem cells resist therapy. To attain this goal, the Ghaffari Laboratory has been investigating metabolic and mitochondrial-related programs and organelle communications in young and aged HSPCs. The Ghaffari lab uses a variety of approaches, including various omics, super resolution imaging, and gene modulation technology combined with genetically modified mouse models and human cells to address these questions.

Ongoing research interests include:

  • Investigating mechanisms that control mitochondria-lysosome communication in normal mouse and human hematopoietic stem cells (HSCs) in aged HSCs and in leukemic stem cells
  • Exploring transcriptional and epigenetic programs that regulate organelle biogenesis in HSPCs and their alteration with age
  • Investigating metabolic and redox regulation of erythroid cell maturation and identifying mechanisms and components of mitochondria-nucleus communication during this process
  • Elucidating mechanisms of apoptosis in beta-thalassemia

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Woojin M. Han

Woojin M. Han, PhD, is an Assistant Professor in the Department of Orthopaedics at the Icahn School of Medicine at Mount Sinai. Dr. Han completed his PhD in bioengineering at the University of Pennsylvania, and his postdoctoral training at the Georgia Institute of Technology. The Han Laboratory develops cell-instructive biomaterials to systematically study how stem cells interact with their surrounding niche in regulating tissue pathophysiology, with a primary focus on skeletal muscle stem (satellite) cells and fibro/adipogenic progenitors. His team also focuses on establishing regenerative therapies for treating injuries and diseases of the musculoskeletal system by harnessing cell-matrix interactions. Dr. Han has previously engineered a synthetic cell-instructive matrix for facilitating the transplantation and engraftment of muscle stem cells in the context of muscle injury and Duchenne muscular dystrophy. By independently tuning multiple material properties through parametric design, Dr. Han and his team has successfully developed a fully synthetic cell delivery platform conducive to muscle stem cell survival, proliferation, migration, and differentiation for targeting limb muscle trauma and dystrophic diaphragms. His research program will continue to integrate multidisciplinary bioengineering concepts to pioneer new technologies for dissecting stem cell-niche interactions and advancing regenerative therapies for musculoskeletal injuries and disorders.

Ongoing research interests include:

  • Engineering niche-mimetic designer platforms to direct muscle stem cell polarity, division, and fate determination for ex vivo muscle stem cell maintenance, expansion, and manufacturing.
  • Understanding the roles of niche-derived biophysical and biochemical cues in regulating muscle stem cell polarity, fate determination, and mechanotransduction in development, aging, and diseases.
  • Developing cell-instructive biomaterials and therapies to treat skeletal muscle injuries and disorders.

Robert A Krauss, PhD

Robert Krauss, PhD, is a Professor of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai and Co-director of the Development, Regeneration, and Stem Cells training area for graduate students. His lab is interested in how niche-derived signals regulate stem cell function, using the skeletal muscle lineage as a model system. His lab showed that cadherins are niche factors that promote quiescence of skeletal muscle stem cells under homeostatic conditions, and regulate activation of these cells in response to injury, thereby facilitating tissue regeneration. His lab uses a variety of approaches, including mouse genetics and molecular cell biology, to address questions about how the muscle stem cell niche is constructed, maintained, and functions. The Krauss Laboratory also studies the Nodal and Hedgehog signaling pathways and how deficiency in these pathways results in the common birth defect, holoprosencephaly.

Ongoing research interests include:

  • Exploring how cadherins regulate cytoskeletal architecture in muscle stem cells to provide structural integrity, mechanosensation, and cell polarity
  • Identifying and analyzing the components of the adherens junction formed between muscle stem cells and their major niche cell, the myofiber
  • Modeling the complex etiology of holoprosencephaly in mice
  • Assessing functional consequences of human mutations involved in holoprosencephaly

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Sarah E. Millar

Sarah E. Millar, PhD, is Director of the Black Family Stem Cell Institute, and Lillian and Henry M. Stratton Professorial Chair in the Departments of Cell, Developmental, and Regenerative Biology, and Dermatology at the Icahn School of Medicine at Mount Sinai. Understanding the molecular and cellular mechanisms regulating the development, patterning, and postnatal renewal of the skin and ectodermal appendage organs such as hair follicles, teeth, and taste papillae, and identifying stem and progenitor cell populations in these organs, is critical for developing new therapies to accelerate wound healing, treat hair loss diseases, repair or replace diseased teeth, and ameliorate taste dysfunction. Research in the Millar Laboratory focuses on cell-cell signaling and epigenetic mechanisms that underlie these processes. In published research, researchers identified Wnt/beta-catenin signaling as a key pathway required for initiating the formation of ectodermal appendages from multipotent cells in mammalian embryos, and in controlling development and patterning of haired versus hairy skin. By analyzing genetic mouse models and tissues from human patients carrying mutations in the WNT10A gene, we showed that Wnt signaling plays a key role in regulating the functions of a wide variety of adult epithelial stem cells, as well as in controlling specialized differentiation programs in palmoplantar skin. We have also identified critical functions for epigenetic regulators including micro-RNAs and chromatin modifiers in skin development and regeneration.

Ongoing research interests include:

  • Investigating mechanisms that cause ectodermal dysplasia in patients with mutations in the WNT10A gene, and testing potential therapeutic strategies
  • Determining the mechanisms that underlie the formation and maintenance of hairy versus hairless skin and regulate hair patterning
  • Delineating the functions of histone deacetylase chromatin modifiers in skin development, stem cells, and cancer
  • Identifying pioneer transcription factors that control development and stem cell activity in skin and oral epithelia

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Kateri Moore, DVM

Kateri Moore, DVM, is a Professor in Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai and a member of The Tisch Cancer Institute. Her research is focused on both normal and reprogrammed hematopoietic stem cells (HSCs). To study normal hematopoiesis, she uses mouse models that allow her to define the characteristics of temporally defined quiescent HSCs during homeostasis. She researches perturbed hematopoiesis and aging HSCs using this model. These studies have implications for understanding the ability of leukemic stem cells and other tumor initiating cells to mimic normal stem cells and remain quiescent, thus evading current therapies. Her lab has reported direct reprogramming of mouse and human fibroblasts into hematopoietic cells using transcription factors. Insights gained during the reprogramming studies have led to the prospective isolation of the immediate precursor cell that give rise to definitive HSC during embryonic development. These studies have broad applications to cancers of the blood and immune system and others that require a stem cell transplant.

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Michael Rendl

Michael Rendl, MD, is a Professor of Cell, Developmental, and Regenerative Biology and Dermatology at the Icahn School of Medicine at Mount Sinai; Director of the NYSTEM Training Program in Stem Cell Biology; and Associate Director of the Black Family Stem Cell Institute. His team studies the formation and function of stem cell niches, using hair follicle formation during skin development and adult hair growth and regeneration as a model system. Dermal papilla (DP) cells are specialized mesenchymal niche cells that instruct hair follicle stem cells and progenitors. His laboratory discovered embryonic DP precursors, defined molecular signatures of embryonic and mature DP cells, and established the essential roles of Wnt signaling and the transcription factor Sox2 for DP functions. The lab has uncovered the DP-related dermal sheath (DS) as a key niche component for hair cycle progression and progenitor pruning, essential for the next wave of stem cell activation. Overall, insights from these studies reveal mechanisms on how stem cell niches function and provide a platform for developing hair regenerative therapies.

Ongoing research interests include:

  • Understanding the molecular controls that regulate DP niche fate and function
  • Investigating DP signals that regulate stem cell and progenitor functions
  • Dissecting DS cellular and molecular mechanisms of hair cycle regulation

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Christopher M. Sturgeon

Christopher M. Sturgeon is an Associate Professor at the Icahn School of Medicine at Mount Sinai. Chris’s lab studies the development of the human hematopoietic system, using the in vitro differentiation of human pluripotent stem cells (hPSC) as a model system. The ability to differentiate hPSC towards a bona fide hematopoietic stem cell (HSC) would be a major step forward for the treatment of patients in need of a suitable donor match. Similarly, hPSCs offer unprecedented access to early embryonic hematopoietic lineages, which may have untapped clinical potential. To harness these possibilities, it is essential to be able to direct the differentiation of hPSCs in a controlled fashion. To that end, Chris’s research has developed defined media approaches, coupled with staged addition of recombinant morphogens such as BMP, WNT, and RA, to recapitulate these early embryonic developmental stages.

Ongoing research interests include:

  • Investigating the molecular mechanisms of hematopoietic development and the immediate precursor to the HSC, hemogenic endothelium
  • Characterizing the translational potential of HSC-independent immune lineages
  • Identifying the developmental trajectory of nascent mesoderm as it differentiates towards blood
  • Understanding the role of RNA splicing in embryonic hematopoiesis

Julie Teruya-Feldstein

Julie Teruya-Feldstein, MD is Director of Hematopathology at the Icahn School of Medicine at Mount Sinai and Mount Sinai Health System.  Understanding the molecular and cellular mechanisms regulating development, growth, of hematopoietic stem cells is critical for developing new therapies and understanding their role after transplantation, immunotherapy and CAR T cell therapy.  The Feldstein Laboratory is defining cellular and immunologic molecular mechanisms into the pathogenesis of hematopoietic cells in the quest for targeted therapeutics of hematologic neoplasms.

 

 

Ongoing research interests include:

  • Defining cellular and immunologic molecular mechanisms into the pathogenesis of hematopoietic cells in the quest for targeted therapeutics of hematologic neoplasms.
  • Biomarkers for diagnosis, prognosis, therapeutic targets, minimal residual disease, role of the bone marrow microenvironment
  • Digital pathology imaging as a tool for research, educational, and clinical purposes
  • Peripheral responses after immunomodulatory therapies

Alexander M. Tsankov

Alexander M. Tsankov, PhD, is an Assistant Professor in Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai. He completed his PhD in electrical engineering and computer science at MIT and his postdoctoral training at the Broad Institute and Harvard University (Alex Meissner and Aviv Regev’s lab). The Tsankov lab overall vision is to use genomics to build data-driven, predictive models that improve diagnosis, find new drug-able pathways, and personalize treatment of patients with lung cancer and respiratory diseases. The lab specializes in next generation sequencing (NGS) technologies (e.g. single-cell transcriptomic, epigenomic, and spatial data) and computational analysis with the goal of unraveling how the underlying regulatory mechanisms, cell-cell interactions, and regenerative lineages have changed in lung disease compared to normal lung tissue homeostasis.

Ongoing research interests include:

  • Using single-cell technologies to reconstruct the regenerative lineages in the human lung and to understand how these have been hijacked in cancer or altered in lung disease
  • Investigating cell-cell interactions and their role on lung regeneration, disease progression, and immunosuppression.
  • Dissecting the cell-type specific regulatory mechanisms underlying normal lung homeostasis and changes that arise in respiratory disease and lung cancer

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