Black Family Stem Cell Institute

Blood-forming Stem Cells

Bone marrow transplantation cures many blood disorders, but a major limitation is the scarcity of compatible blood forming (hematopoietic) stem cells and the challenges to maintain and expand these cells ex vivo for clinical use.

Blood-forming stem cells produce all the cells in the blood, including red blood cells, which carry oxygen to the tissues; white blood cells, which constitute the immune system of the body; and platelets, which participate in blood clotting and coagulation.

Investigators at the Black Family Stem Cell Institute focus on elucidating developmental, epigenetic, redox-mediated, and metabolic mechanisms that govern hematopoietic stem cell properties to be exploited for their maintenance and their expansion ex vivo. Ongoing clinical trials are attempting to translate some of these findings in patients.

Others focus on expanding cord blood hematopoietic stem cells or on generating new hematopoietic stem cells by differentiating patient-derived pluripotent stem cells or direct reprograming of patient cells for future transplantation therapies. These in vitro models of blood, including immune disorders, will help produce hematopoietic stem cells and overall blood, correcting genetic aberrations and identifying underlying mechanisms of diseased stem cells. We will also be able to use them for drug screening. Another promising line of investigation is dedicated to exploring mechanisms that promote aging of hematopoietic stem cells.

Aging is thought to lead to alterations of hematopoietic stem cell properties that increase the risk of blood cancers and immune deficiencies of the elderly. Ongoing efforts emphasize exposing processes involved in hematopoietic stem cell aging. Our overarching goal is to develop means to revert or delay blood stem cell aging for a longer, healthier life.

Investigators with a major focus in blood-forming stem cells include:

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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James J. Bieker, PhD

James J. Bieker, PhD, is a Professor in the Department of Cell, Developmental, and Regenerative Biology at the Icahn School of Medicine at Mount Sinai. The laboratory's interest is in the transcriptional regulation of red blood cell-specific gene expression, and in identifying the molecular events that confer the ability to express lineage-specific genes in uncommitted, pluripotent hematopoietic stem cells. These issues are being addressed by the functional analysis of a novel, erythroid-specific gene that the Bieker Laboratory identified a number of years ago named erythroid Krüppel-like factor; EKLF. Biochemical, molecular, cellular, developmental, and genetic studies in mice and humans have established that EKLF is an essential component required for globin switching and completion of the definitive erythroid program.

Using our model system, we aim to disentangle genotype from phenotype and cell-type and identify disease relevant common and unique pathways that hold promise for future therapies.

Ongoing research interests include:

  • Analyzing EKLF protein/protein interactions and how they result in altered transcriptional and epigenetic changes at target loci
  • Determining how molecular controls converge to regulate late events in erythropoiesis, particularly enucleation
  • Analyzing EKLF upstream regulators to explain its exquisite tissue-restricted expression pattern, and to possibly link alteration of its expression level to aberrant red cell biology
  • Determining the mechanism by which a human mutation in EKLF leads to congenital dyserythropoietic anemia.

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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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Ronald Hoffman, MD, is the Albert A. and Vera G. List Professor of Medicine at the Icahn School of Medicine at Mount Sinai. He is a member of The Tisch Cancer Institute. His team has two areas of interest. One deals with the expansion of the number of marrow repopulating cells present in cord blood for transplantation into humans undergoing allogeneic stem cell transplantation for refractory hematological malignancies. This expansion strategy uses histone deacetylase inhibitors. The team is attempting to understand the mechanism underlying this ex vivo stem cell expansion technology, and is actively evaluating the clinical potential of this expanded cell product in a phase I clinical trial. The second area of interest deals with the blood cancer myelofibrosis. Dr. Hoffman and his team are characterizing the malignant myelofibrosis stem cells and their progeny and the consequence of their interactions with the marrow and splenic microenvironments. With this growing body of information the group is identifying novel agents to deplete myelofibrosis stem cells. These agents are currently being evaluated in a series of phase I/II clinical trials in a clinical consortium including 11 institutions in the United States and Canada, headed by Dr. Hoffman.

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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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Eirini Papapetrou, MD, PhD

Eirini Papapetrou, MD, PhD, is an Associate Professor of Oncological Sciences, Hematology, and Medical Oncology at the Icahn School of Medicine at Mount Sinai; and Associate Director of the Pluripotent Stem Cell Engineering Core. Her laboratory pioneered the modeling of blood cancers with human-induced pluripotent stem cell (iPSC). Specifically, her lab developed the first iPSC models of myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia by reprogramming patient cells and by correcting and introducing mutations using CRISPR/Cas9-mediated gene editing. Dr. Papapetrou’s research program combines techniques and principles from stem cell research, cancer biology, and hematopoiesis with the goal of understanding disease mechanisms and identifying new therapeutic targets for hematologic malignancies. The unifying theme of the lab’s projects is the creation of genetically precise isogenic iPSC models of myeloid cancers and exploitation of the unique capabilities they offer for genotype-to-phenotype studies, interrogation of the effects of oncogenic mutations with integrative genomics analyses in a faithful cellular and genomic environment and genetic (CRISPR), and small molecule screens for drug repurposing or drug discovery. Dr. Papapetrou is the recipient of several awards, including the American Society of Gene and Cell Therapy Outstanding New Investigator Award, Damon Runyon-Rachleff Innovation Award, American Society of Hematology Scholar Award, Pershing Square Sohn Prize, and Leukemia and Lymphoma Society Scholar award, among others. She is an elected member of the American Society for Clinical Investigation.

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Christoph Schaniel, PhD

Christoph Schaniel, PhD, is an Assistant Professor in the Department of Pharmacological Sciences, the Department of Cell, Developmental and Regenerative Biology, and a member of the Mount Sinai Institute for System Biomedicine. His research is centered on understanding the cellular and molecular nature of hematopoietic stem cells (HSCs) in health and disease. He helped develop a clinical ex vivo expansion and cryopreservation process of umbilical cord blood HSCs for allogenic stem cell transplantation in refractory hematological malignancies that is being evaluated in a clinical trial (in collaboration with Ronald Hoffman, MD, and Camelia Iancu-Rubin, PhD). Additionally, he is investigating the mechanism and clinical applicability of direct reprogramming of HSCs from somatic cells for cell replacement therapies (together with Kateri A. Moore, DVM). Other research focuses on the effect of valproic acid on normal vs. malignant HSCs, the underlying pathologies of hematological malignancies and cancers using human primary stem cells, and induced pluripotent stem cells (PSCs). He is also invested in various projects aimed at understanding the mechanisms of cardiovascular diseases and drug action, responses, and toxicity in individuals using induced PSCs with the goal of advancing and developing precise and personalized therapeutic treatments.

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