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Our Faculty
David Scadden, M.D.
Dr. David Scadden is the Gerald and Darlene Jordan Professor of Medicine at Harvard University. He is Professor and Chair emeritus of the Harvard University Department of Stem Cell and Regenerative Biology. He is a co-founding co-director of the Harvard Stem Cell Institute with Prof. Douglas Melton. He is a hematologist/oncologist at the Massachusetts General Hospital where he founded and directs the Center for Regenerative Medicine and previously led the Hematologic Malignancies Program of the MGH Cancer Center. He is a member/fellow of the National Academy of Medicine, the American Academy of Arts and Sciences, the American Association for the Advancement of Science, the American College of Physicians and is a former member of the Board of External Experts for the National Heart, Lung and Blood Institute and the National Cancer Institute’s Board of Scientific Counselors. He is an Affiliate Member of the Broad Institute of Harvard and MIT. Scientific discoveries become patient therapies through companies. Therefore, he is involved in biotechnology companies, founding the public companies Fate Therapeutics and Magenta Therapeutics. He serves as a Director of Agios Pharmaceuticals, Magenta Therapeutics, and Editas Medicines.
The Scadden lab emphasizes using multidisciplinary approaches to define novel therapies for blood diseases. His lab has been recognized for pioneering work in the bone marrow microenvironment, defining that alteration of stromal components of the stem cell niche can induce hematologic malignancies and discovering novel methods to improve hematopoietic stem cell transplantation. The lab has demonstrated previously unrecognized constraints on blood stem cell plasticity and a means by which altering leukemic cell metabolism can overcome differentiation blockade leading to cancer cell death. The emphasis of the lab is exploring the fundamental biology of blood cell production while prioritizing areas where insights may lead to therapeutics.
- Professor of Stem Cell and Regenerative Biology
- Gerald and Darlene Jordan Professor of Medicine
Harvard University - Co-Director
Harvard Stem Cell Institute - Director
Center for Regenerative Medicine, Massachusetts General Hospital - Past Co-Chair (2008-2013)
Harvard Department of Stem Cell and Regenerative Biology - Past Chair (2013-2018)
Harvard Department of Stem Cell and Regenerative Biology
Contact Information
7 Divinity Avenue
Cambridge, MA 02138
Featured Publications
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2019. A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell. 177(7):1915-1932.e16. Pubmed: 31130381 DOI:S0092-8674(19)30459-3 Baryawno N, Przybylski D, Kowalczyk MS, Kfoury Y, Severe N, Gustafsson K, Kokkaliaris KD, Mercier F, Tabaka M, Hofree M, Dionne D, Papazian A, Lee D, Ashenberg O, Subramanian A, Vaishnav ED, Rozenblatt-Rosen O, Regev A, Scadden DT. 2019. A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell. 177(7):1915-1932.e16. Pubmed: 31130381 DOI:S0092-8674(19)30459-3 Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer.Copyright © 2019 Elsevier Inc. All rights reserved. -
Shah NJ, Mao AS, Shih TY, Kerr MD, Sharda A, Raimondo TM, Weaver JC, Vrbanac VD, Deruaz M, Tager AM, Mooney DJ, Scadden DT. 2019. An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation. Nature biotechnology. 37(3):293-302. Pubmed: 30742125 DOI:10.1038/s41587-019-0017-2 Shah NJ, Mao AS, Shih TY, Kerr MD, Sharda A, Raimondo TM, Weaver JC, Vrbanac VD, Deruaz M, Tager AM, Mooney DJ, Scadden DT. 2019. An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation. Nature biotechnology. 37(3):293-302. Pubmed: 30742125 DOI:10.1038/s41587-019-0017-2 Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for multiple disorders, but deficiency and dysregulation of T cells limit its utility. Here we report a biomaterial-based scaffold that mimics features of T cell lymphopoiesis in the bone marrow. The bone marrow cryogel (BMC) releases bone morphogenetic protein-2 to recruit stromal cells and presents the Notch ligand Delta-like ligand-4 to facilitate T cell lineage specification of mouse and human hematopoietic progenitor cells. BMCs subcutaneously injected in mice at the time of HSCT enhanced T cell progenitor seeding of the thymus, T cell neogenesis and diversification of the T cell receptor repertoire. Peripheral T cell reconstitution increased ~6-fold in mouse HSCT and ~2-fold in human xenogeneic HSCT. Furthermore, BMCs promoted donor CD4 regulatory T cell generation and improved survival after allogeneic HSCT. In comparison to adoptive transfer of T cell progenitors, BMCs increased donor chimerism, T cell generation and antigen-specific T cell responses to vaccination. BMCs may provide an off-the-shelf approach for enhancing T cell regeneration and mitigating graft-versus-host disease in HSCT. -
Yu VWC, Yusuf RZ, Oki T, Wu J, Saez B, Wang X, Cook C, Baryawno N, Ziller MJ, Lee E, Gu H, Meissner A, Lin CP, Kharchenko PV, Scadden DT. 2017. Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells. Cell. 168(5):944-945. Pubmed: 28235203 DOI:S0092-8674(17)30188-5 Yu VWC, Yusuf RZ, Oki T, Wu J, Saez B, Wang X, Cook C, Baryawno N, Ziller MJ, Lee E, Gu H, Meissner A, Lin CP, Kharchenko PV, Scadden DT. 2017. Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells. Cell. 168(5):944-945. Pubmed: 28235203 DOI:S0092-8674(17)30188-5 Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of—and molecular basis for—heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted. -
Sykes DB, Kfoury YS, Mercier FE, Wawer MJ, Law JM, Haynes MK, Lewis TA, Schajnovitz A, Jain E, Lee D, Meyer H, Pierce KA, Tolliday NJ, Waller A, Ferrara SJ, Eheim AL, Stoeckigt D, Maxcy KL, Cobert JM, Bachand J, Szekely BA, Mukherjee S, Sklar LA, Kotz JD, Clish CB, Sadreyev RI, Clemons PA, Janzer A, Schreiber SL, Scadden DT. 2016. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell. 167(1):171-186.e15. Pubmed: 27641501 DOI:S0092-8674(16)31154-0 Sykes DB, Kfoury YS, Mercier FE, Wawer MJ, Law JM, Haynes MK, Lewis TA, Schajnovitz A, Jain E, Lee D, Meyer H, Pierce KA, Tolliday NJ, Waller A, Ferrara SJ, Eheim AL, Stoeckigt D, Maxcy KL, Cobert JM, Bachand J, Szekely BA, Mukherjee S, Sklar LA, Kotz JD, Clish CB, Sadreyev RI, Clemons PA, Janzer A, Schreiber SL, Scadden DT. 2016. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell. 167(1):171-186.e15. Pubmed: 27641501 DOI:S0092-8674(16)31154-0 While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.Copyright © 2016 Elsevier Inc. All rights reserved. -
Palchaudhuri R, Saez B, Hoggatt J, Schajnovitz A, Sykes DB, Tate TA, Czechowicz A, Kfoury Y, Ruchika F, Rossi DJ, Verdine GL, Mansour MK, Scadden DT. 2016. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nature biotechnology. 34(7):738-45. Pubmed: 27272386 DOI:10.1038/nbt.3584 Palchaudhuri R, Saez B, Hoggatt J, Schajnovitz A, Sykes DB, Tate TA, Czechowicz A, Kfoury Y, Ruchika F, Rossi DJ, Verdine GL, Mansour MK, Scadden DT. 2016. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nature biotechnology. 34(7):738-45. Pubmed: 27272386 DOI:10.1038/nbt.3584 Hematopoietic stem cell transplantation (HSCT) offers curative therapy for patients with hemoglobinopathies, congenital immunodeficiencies, and other conditions, possibly including AIDS. Autologous HSCT using genetically corrected cells would avoid the risk of graft-versus-host disease (GVHD), but the genotoxicity of conditioning remains a substantial barrier to the development of this approach. Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45-saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45-SAP completely avoided neutropenia and anemia, spared bone marrow and thymic niches, enabling rapid recovery of T and B cells, preserved anti-fungal immunity, and had minimal overall toxicity. This non-genotoxic conditioning method may provide an attractive alternative to current conditioning regimens for HSCT in the treatment of non-malignant blood diseases. -
Silberstein L, Goncalves KA, Kharchenko PV, Turcotte R, Kfoury Y, Mercier F, Baryawno N, Severe N, Bachand J, Spencer JA, Papazian A, Lee D, Chitteti BR, Srour EF, Hoggatt J, Tate T, Lo Celso C, Ono N, Nutt S, Heino J, Sipilä K, Shioda T, Osawa M, Lin CP, Hu GF, Scadden DT. 2016. Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators. Cell stem cell. 19(4):530-543. Pubmed: 27524439 DOI:S1934-5909(16)30199-0 Silberstein L, Goncalves KA, Kharchenko PV, Turcotte R, Kfoury Y, Mercier F, Baryawno N, Severe N, Bachand J, Spencer JA, Papazian A, Lee D, Chitteti BR, Srour EF, Hoggatt J, Tate T, Lo Celso C, Ono N, Nutt S, Heino J, Sipilä K, Shioda T, Osawa M, Lin CP, Hu GF, Scadden DT. 2016. Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators. Cell stem cell. 19(4):530-543. Pubmed: 27524439 DOI:S1934-5909(16)30199-0 Physiological stem cell function is regulated by secreted factors produced by niche cells. In this study, we describe an unbiased approach based on the differential single-cell gene expression analysis of mesenchymal osteolineage cells close to, and further removed from, hematopoietic stem/progenitor cells (HSPCs) to identify candidate niche factors. Mesenchymal cells displayed distinct molecular profiles based on their relative location. We functionally examined, among the genes that were preferentially expressed in proximal cells, three secreted or cell-surface molecules not previously connected to HSPC biology-the secreted RNase angiogenin, the cytokine IL18, and the adhesion molecule Embigin-and discovered that all of these factors are HSPC quiescence regulators. Therefore, our proximity-based differential single-cell approach reveals molecular heterogeneity within niche cells and can be used to identify novel extrinsic stem/progenitor cell regulators. Similar approaches could also be applied to other stem cell/niche pairs to advance the understanding of microenvironmental regulation of stem cell function.Copyright © 2016 Elsevier Inc. All rights reserved. -
Scadden DT. 2016. Blood and Bone. The New England journal of medicine. 374(19):1891-3. Pubmed: 27168440 DOI:10.1056/NEJMcibr1601737 Scadden DT. 2016. Blood and Bone. The New England journal of medicine. 374(19):1891-3. Pubmed: 27168440 DOI:10.1056/NEJMcibr1601737 -
Wang YH, Israelsen WJ, Lee D, Yu VWC, Jeanson NT, Clish CB, Cantley LC, Vander Heiden MG, Scadden DT. 2014. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell. 158(6):1309-1323. Pubmed: 25215489 DOI:S0092-8674(14)01038-1 Wang YH, Israelsen WJ, Lee D, Yu VWC, Jeanson NT, Clish CB, Cantley LC, Vander Heiden MG, Scadden DT. 2014. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell. 158(6):1309-1323. Pubmed: 25215489 DOI:S0092-8674(14)01038-1 The balance between oxidative and nonoxidative glucose metabolism is essential for a number of pathophysiological processes. By deleting enzymes that affect aerobic glycolysis with different potencies, we examine how modulating glucose metabolism specifically affects hematopoietic and leukemic cell populations. We find that a deficiency in the M2 pyruvate kinase isoform (PKM2) reduces the levels of metabolic intermediates important for biosynthesis and impairs progenitor function without perturbing hematopoietic stem cells (HSCs), whereas lactate dehydrogenase A (LDHA) deletion significantly inhibits the function of both HSCs and progenitors during hematopoiesis. In contrast, leukemia initiation by transforming alleles putatively affecting either HSCs or progenitors is inhibited in the absence of either PKM2 or LDHA, indicating that the cell-state-specific responses to metabolic manipulation in hematopoiesis do not apply to the setting of leukemia. This finding suggests that fine-tuning the level of glycolysis may be explored therapeutically for treating leukemia while preserving HSC function.Copyright © 2014 Elsevier Inc. All rights reserved. -
Scadden DT. 2014. Nice neighborhood: emerging concepts of the stem cell niche. Cell. 157(1):41-50. Pubmed: 24679525 DOI:S0092-8674(14)00205-0 Scadden DT. 2014. Nice neighborhood: emerging concepts of the stem cell niche. Cell. 157(1):41-50. Pubmed: 24679525 DOI:S0092-8674(14)00205-0 No metazoan cell survives on its own, absent the signals and support of its milieu. For multicellular life with specialized tissues to persist, organization is everything and so defining the association of position with cell state is critical to understanding how tissues function, maintain, and repair. This review focuses specifically on place for progenitor and stem cells. Especially emphasized are hematopoietic cells that balance free movement and stable position and where concepts of regulatory interrelationships have been shown with some precision. It reviews classical and emerging concepts of the niche, particularly considering how niche functions may participate in neoplastic disease.Copyright © 2014 Elsevier Inc. All rights reserved. -
Morrison SJ, Scadden DT. 2014. The bone marrow niche for haematopoietic stem cells. Nature. 505(7483):327-34. Pubmed: 24429631 DOI:10.1038/nature12984 Morrison SJ, Scadden DT. 2014. The bone marrow niche for haematopoietic stem cells. Nature. 505(7483):327-34. Pubmed: 24429631 DOI:10.1038/nature12984 Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments. -
Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, Ebert BL, Al-Shahrour F, Hasserjian RP, Scadden EO, Aung Z, Matza M, Merkenschlager M, Lin C, Rommens JM, Scadden DT. 2010. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 464(7290):852-7. Pubmed: 20305640 DOI:10.1038/nature08851 Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, Ebert BL, Al-Shahrour F, Hasserjian RP, Scadden EO, Aung Z, Matza M, Merkenschlager M, Lin C, Rommens JM, Scadden DT. 2010. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 464(7290):852-7. Pubmed: 20305640 DOI:10.1038/nature08851 Mesenchymal cells contribute to the 'stroma' of most normal and malignant tissues, with specific mesenchymal cells participating in the regulatory niches of stem cells. By examining how mesenchymal osteolineage cells modulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors, but not in mature osteoblasts, disrupts the integrity of haematopoiesis. Myelodysplasia resulted and acute myelogenous leukaemia emerged that had acquired several genetic abnormalities while having intact Dicer1. Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletion showed reduced expression of Sbds, the gene mutated in Schwachman-Bodian-Diamond syndrome-a human bone marrow failure and leukaemia pre-disposition condition. Deletion of Sbds in mouse osteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, perturbation of specific mesenchymal subsets of stromal cells can disorder differentiation, proliferation and apoptosis of heterologous cells, and disrupt tissue homeostasis. Furthermore, primary stromal dysfunction can result in secondary neoplastic disease, supporting the concept of niche-induced oncogenesis. -
Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, Côté D, Rowe DW, Lin CP, Scadden DT. 2009. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 457(7225):92-6. Pubmed: 19052546 DOI:10.1038/nature07434 Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, Côté D, Rowe DW, Lin CP, Scadden DT. 2009. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 457(7225):92-6. Pubmed: 19052546 DOI:10.1038/nature07434 Stem cells reside in a specialized, regulatory environment termed the niche that dictates how they generate, maintain and repair tissues. We have previously documented that transplanted haematopoietic stem and progenitor cell populations localize to subdomains of bone-marrow microvessels where the chemokine CXCL12 is particularly abundant. Using a combination of high-resolution confocal microscopy and two-photon video imaging of individual haematopoietic cells in the calvarium bone marrow of living mice over time, we examine the relationship of haematopoietic stem and progenitor cells to blood vessels, osteoblasts and endosteal surface as they home and engraft in irradiated and c-Kit-receptor-deficient recipient mice. Osteoblasts were enmeshed in microvessels and relative positioning of stem/progenitor cells within this complex tissue was nonrandom and dynamic. Both cell autonomous and non-autonomous factors influenced primitive cell localization. Different haematopoietic cell subsets localized to distinct locations according to the stage of differentiation. When physiological challenges drove either engraftment or expansion, bone-marrow stem/progenitor cells assumed positions in close proximity to bone and osteoblasts. Our analysis permits observing in real time, at a single cell level, processes that previously have been studied only by their long-term outcome at the organismal level. -
Adams GB, Martin RP, Alley IR, Chabner KT, Cohen KS, Calvi LM, Kronenberg HM, Scadden DT. 2007. Therapeutic targeting of a stem cell niche. Nature biotechnology. 25(2):238-43. Pubmed: 17237769 Adams GB, Martin RP, Alley IR, Chabner KT, Cohen KS, Calvi LM, Kronenberg HM, Scadden DT. 2007. Therapeutic targeting of a stem cell niche. Nature biotechnology. 25(2):238-43. Pubmed: 17237769 The specialized microenvironment or niche where stem cells reside provides regulatory input governing stem cell function. We tested the hypothesis that targeting the niche might improve stem cell-based therapies using three mouse models that are relevant to clinical uses of hematopoietic stem (HS) cells. We and others previously identified the osteoblast as a component of the adult HS cell niche and established that activation of the parathyroid hormone (PTH) receptor on osteoblasts increases stem cell number. Here we show that pharmacologic use of PTH increases the number of HS cells mobilized into the peripheral blood for stem cell harvests, protects stem cells from repeated exposure to cytotoxic chemotherapy and expands stem cells in transplant recipients. These data provide evidence that the niche may be an attractive target for drug-based stem cell therapeutics. -
Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC, Kos CH, Pollak MR, Brown EM, Scadden DT. 2006. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature. 439(7076):599-603. Pubmed: 16382241 Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC, Kos CH, Pollak MR, Brown EM, Scadden DT. 2006. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature. 439(7076):599-603. Pubmed: 16382241 During mammalian ontogeny, haematopoietic stem cells (HSCs) translocate from the fetal liver to the bone marrow, where haematopoiesis occurs throughout adulthood. Unique features of bone that contribute to a microenvironmental niche for stem cells might include the known high concentration of calcium ions at the HSC-enriched endosteal surface. Cells respond to extracellular ionic calcium concentrations through the seven-transmembrane-spanning calcium-sensing receptor (CaR), which we identified as being expressed on HSCs. Here we show that, through the CaR, the simple ionic mineral content of the niche may dictate the preferential localization of adult mammalian haematopoiesis in bone. Antenatal mice deficient in CaR had primitive haematopoietic cells in the circulation and spleen, whereas few were found in bone marrow. CaR-/- HSCs from fetal liver were normal in number, in proliferative and differentiative function, and in migration and homing to the bone marrow. Yet they were highly defective in localizing anatomically to the endosteal niche, behaviour that correlated with defective adhesion to the extracellular matrix protein, collagen I. CaR has a function in retaining HSCs in close physical proximity to the endosteal surface and the regulatory niche components associated with it. -
Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT. 2006. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 443(7110):421-6. Pubmed: 16957735 Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT. 2006. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 443(7110):421-6. Pubmed: 16957735 Stem-cell ageing is thought to contribute to altered tissue maintenance and repair. Older humans experience increased bone marrow failure and poorer haematologic tolerance of cytotoxic injury. Haematopoietic stem cells (HSCs) in older mice have decreased per-cell repopulating activity, self-renewal and homing abilities, myeloid skewing of differentiation, and increased apoptosis with stress. Here we report that the cyclin-dependent kinase inhibitor p16INK4a, the level of which was previously noted to increase in other cell types with age, accumulates and modulates specific age-associated HSC functions. Notably, in the absence of p16INK4a, HSC repopulating defects and apoptosis were mitigated, improving the stress tolerance of cells and the survival of animals in successive transplants, a stem-cell-autonomous tissue regeneration model. Inhibition of p16INK4a may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue. -
Scadden DT. 2006. The stem-cell niche as an entity of action. Nature. 441(7097):1075-9. Pubmed: 16810242 Scadden DT. 2006. The stem-cell niche as an entity of action. Nature. 441(7097):1075-9. Pubmed: 16810242 Stem-cell populations are established in 'niches'--specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics. -
Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 425(6960):841-6. Pubmed: 14574413 Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 425(6960):841-6. Pubmed: 14574413 Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies. -
Shen H, Cheng T, Olszak I, Garcia-Zepeda E, Lu Z, Herrmann S, Fallon R, Luster AD, Scadden DT. 2001. CXCR-4 desensitization is associated with tissue localization of hemopoietic progenitor cells. Journal of immunology (Baltimore, Md. : 1950). 166(8):5027-33. Pubmed: 11290783 Shen H, Cheng T, Olszak I, Garcia-Zepeda E, Lu Z, Herrmann S, Fallon R, Luster AD, Scadden DT. 2001. CXCR-4 desensitization is associated with tissue localization of hemopoietic progenitor cells. Journal of immunology (Baltimore, Md. : 1950). 166(8):5027-33. Pubmed: 11290783 The chemokine stroma-derived factor (SDF)-1, and its receptor, CXCR-4, have been shown to be essential for the translocation of hemopoietic stem cells from the fetal liver to the bone marrow (BM). We hypothesized that if CXCR-4 plays a crucial role in the localization of human hemopoiesis, stem cells from distinct tissue sources should demonstrate distinct CXCR-4 expression or signaling profiles. CD34(+) cells from BM were compared with blood: either mobilized peripheral blood or umbilical cord blood. Unexpectedly, significantly higher levels of CXCR-4 surface expression on CD34(+) cells from blood sources, mobilized peripheral blood, or cord blood were observed compared with BM (p = 0.0005 and p = 0.002, respectively). However, despite lower levels of CXCR-4, responsiveness of the cells to SDF-1 as measured by either calcium flux or transmigration was proportionally greatest in cells derived from BM. Further, internalization of CXCR-4 in response to ligand, associated with receptor desensitization, was significantly lower on BM-derived cells. Therefore, preserved chemokine receptor signaling was highly associated with marrow rather than blood localization. To test the functional effects of perturbing CXCR-4 signaling, adult mice were exposed to the methionine-SDF-1beta analog that induces prolonged down-regulation/desensitization of CXCR-4 and observed mobilization of Lin(-), Sca-1(+), Thy-1(low), and c-kit(+) hemopoietic progenitor cells to the peripheral blood with a >30-fold increase compared with PBS control (p = 0.0007 day 1 and p = 0.004 day 2). These data demonstrate that CXCR-4 expression and function can be dissociated in progenitor cells and that desensitization of CXCR-4 induces stem cell entry into the circulation. -
Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT. 2000. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science (New York, N.Y.). 287(5459):1804-8. Pubmed: 10710306 Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT. 2000. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science (New York, N.Y.). 287(5459):1804-8. Pubmed: 10710306 Relative quiescence is a defining characteristic of hematopoietic stem cells, while their progeny have dramatic proliferative ability and inexorably move toward terminal differentiation. The quiescence of stem cells has been conjectured to be of critical biologic importance in protecting the stem cell compartment, which we directly assessed using mice engineered to be deficient in the G1 checkpoint regulator, cyclin-dependent kinase inhibitor, p21cip1/waf1 (p21). In the absence of p21, hematopoietic stem cell proliferation and absolute number were increased under normal homeostatic conditions. Exposing the animals to cell cycle-specific myelotoxic injury resulted in premature death due to hematopoietic cell depletion. Further, self-renewal of primitive cells was impaired in serially transplanted bone marrow from p21-/- mice, leading to hematopoietic failure. Therefore, p21 is the molecular switch governing the entry of stem cells into the cell cycle, and in its absence, increased cell cycling leads to stem cell exhaustion. Under conditions of stress, restricted cell cycling is crucial to prevent premature stem cell depletion and hematopoietic death. -
Berardi AC, Wang A, Levine JD, Lopez P, Scadden DT. 1995. Functional isolation and characterization of human hematopoietic stem cells. Science (New York, N.Y.). 267(5194):104-8. Pubmed: 7528940 Berardi AC, Wang A, Levine JD, Lopez P, Scadden DT. 1995. Functional isolation and characterization of human hematopoietic stem cells. Science (New York, N.Y.). 267(5194):104-8. Pubmed: 7528940 Hematopoietic cells differentiate in steps marked by the acquisition or loss of specific phenotypic characteristics. Human bone marrow cells that were responsive to the early-acting cytokines Kit ligand and interleukin-3 were forced to a metabolic death. The subfraction remaining represented 1 in 10(5) bone marrow mononuclear cells, were determined to be quiescent by cell cycle analysis, and had a stem cell immunophenotype. The cells were highly enriched for long-term culture-initiating cells, were capable of secondary colony formation, and produced both myeloid and lymphoid progeny. Thus, this technically simple strategy led to the efficient purification of cells with characteristics of hematopoietic stem cells. -
Severe N, Karabacak NM, Gustafsson K, Baryawno N, Courties G, Kfoury Y, Kokkaliaris KD, Rhee C, Lee D, Scadden EW, Garcia-Robledo JE, Brouse T, Nahrendorf M, Toner M, Scadden DT. 2019. Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping. Cell stem cell. 25(4):570-583.e7. Pubmed: 31279774 DOI:S1934-5909(19)30267-X Severe N, Karabacak NM, Gustafsson K, Baryawno N, Courties G, Kfoury Y, Kokkaliaris KD, Rhee C, Lee D, Scadden EW, Garcia-Robledo JE, Brouse T, Nahrendorf M, Toner M, Scadden DT. 2019. Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping. Cell stem cell. 25(4):570-583.e7. Pubmed: 31279774 DOI:S1934-5909(19)30267-X Stromal cell populations that maintain hematopoietic stem and progenitor cells (HSPCs) are generally characterized in steady-state conditions. Here, we report a comprehensive atlas of bone marrow stromal cell subpopulations under homeostatic and stress conditions using mass cytometry (CyTOF)-based single-cell protein analysis. We identified 28 subsets of non-hematopoietic cells during homeostasis, 14 of which expressed hematopoietic regulatory factors. Irradiation-based conditioning for HSPC transplantation led to the loss of most of these populations, including the LeptinR and Nestin subsets. In contrast, a subset expressing Ecto-5'-nucleotidase (CD73) was retained and a specific CD73NGFR population expresses high levels of cytokines during homeostasis and stress. Genetic ablation of CD73 compromised HSPC transplantation in an acute setting without long-term changes in bone marrow HSPCs. Thus, this protein-based expression mapping reveals distinct sets of stromal cells in the bone marrow and how they change in clinically relevant stress settings to contribute to early stages of hematopoietic regeneration.Copyright © 2019 Elsevier Inc. All rights reserved.