Biology subjects

Weissman, I. L.

Publications and source records attributed to Weissman, I. L..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

P66 is a bacterial mimic of CD47 that binds the anti-phagocytic receptor SIRPα and facilitates macrophage evasion by Borrelia burgdorferi

Summary ParagraphInnate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "dont eat me" signaling axis between CD47 (ligand) and SIRP (receptor). We identified a protein, P66, on the surface of Borrelia burgdorferi that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRP. Expression of the gene encoding the protein is required for bacteria to bind SIRP or a high-affinity CD47 reagent. Genetic deletion of p66 increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by B. burgdorferi inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRP. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.

immunology↗

bioRxiv2023

SIRPα controls CD47-dependent platelet clearance in mice and humans

Over the last decade, more data has revealed that increased surface expression of the "dont eat me" CD47 protein on cancer cells plays a role in immune evasion and tumor progression, with CD47 blockade emerging as a new therapy in immuno-oncology. CD47 is critical in regulating cell homeostasis and clearance, as binding of CD47 to the inhibitory receptor SIRP can prevent phagocytosis and macrophage-mediated cell clearance. The purpose of this study was to examine the role of the CD47-SIRP signal in platelet homeostasis and clearance. Therapeutic reagents targeting the CD47-SIRP axis are very promising for treatment of hematologic malignancies and solid tumors, but lead to transient anemia or thrombocytopenia in a subset of patients. We found that platelet homeostatic clearance is regulated through the CD47-SIRP axis and that therapeutic blockade to disrupt this interaction in mice and in humans has a significant impact on platelet levels. Furthermore, we identified genetic variations at the SIRPA locus that impact platelet levels in humans such that higher SIRPA gene expression is associated with higher platelet levels. SIRPA expression at either end of the normal range may affect clinical outcomes of treatment with anti-CD47 therapy. Key pointsO_LIPlatelet homeostasis is regulated through the CD47-SIRP axis and therapeutic blockade to disrupt this interaction impacts platelet levels C_LIO_LICommon genetic variants at SIRPA locus associate with platelet levels C_LI

immunology↗

bioRxiv2023

Engineered CD47 protects T cells for enhanced antitumor immunity

Adoptively transferred T cells and agents designed to block the CD47/SIRP axis are promising antitumor therapeutics, which activate distinct arms of the immune system. We administered anti-CD47 (CD47) with adoptively transferred T cells with the goal of enhancing antitumor efficacy but observed rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors, which blunted therapeutic benefit. CD47 mediated CAR T clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered a CD47 variant (47E) that engaged SIRP and provided a "dont-eat-me" signal that was not blocked by CD47 antibodies. TCR or CAR T cells expressing 47E were resistant to clearance by macrophages following CD47, and mediated significant, sustained macrophage recruitment into the TME. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy resulted in synergistic enhancement in antitumor efficacy. This work identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T cell directed therapeutics with those designed to activate macrophages. It further delivers a therapeutic approach capable of simultaneously harnessing the antitumor effects of T cells and macrophages that manifests markedly enhanced potency against solid tumors.

bioengineering↗

bioRxiv2022

Secretoglobin family 1D member 2 (SCGB1D2) protein inhibits growth of Borrelia burgdorferi and affects susceptibility to Lyme disease

Lyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The disease can initially manifest as an erythema migrans rash and, if able to evade the host immune defenses, can progress into a secondary stage chronic disease with debilitating physical or neurological manifestations1,2. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Here we show a novel host defense mechanism against Lyme disease in humans. Using epidemiological and genetic data from FinnGen, we identify a common missense variant at the gene encoding for Secretoglobin family 1D member 2 (SCGB1D2) protein that increases the susceptibility for Lyme disease. The genetic variant changes proline at position 53 to leucine and is predicted as deleterious. Consequently, we validate the dysfunction of this protein variant using live Borrelia burgdorferi (Bb). Recombinant reference SCGB1D2 protein inhibits the growth of Bb twice as effectively as the recombinant SCGB1D2 P53L deleterious missense variant. Together, these data suggest that SCGB1D2 is a host defense factor present in the skin, sweat, and other secretions which protects against Bb infection. This finding provides a novel therapeutic avenue for drug development to prevent and treat Lyme disease.

genetics↗

bioRxiv2022

Novel Association of Lyme Disease, Age, and Atopic Dermatitis

Borrelia burgdorferi (B. burgdorferi) is a bacterial spirochete that can cause Lyme disease after infecting a susceptible host. Immune responses to the bacteria are highly variable and host specific. The murine substrain, C3H/HeJ, is a frequently utilized mouse model of Lyme disease. In this study, we sought to investigate the correlation of age with onset and severity of dermatitis, both in mice infected with B. burgdorferi as well as humans who have had a diagnosis of Lyme disease. Female C3H/HeJ mice aged 6-8 weeks, 1 year, or 2 years were infected intraperitoneally with 105 B. burgdorferi. Dermatitis of the tail was evaluated by gross examination and histology. Additional female C3H/HeJ and C57BL/6J mice aged 5 weeks were injected intradermally with 105 B. burgdorferi containing the luciferase reporter gene then analyzed under in vivo imaging. Human data via electronic health records of 342,499 Finnish individuals was tested and analyzed for associations between Lyme disease and atopic dermatitis. Dermatitis worsened over the course of untreated infection, with ulceration, hemorrhaging, flaking, hair loss, and dark lesions as well as spongiosis and acanthosis. These features of dermatitis were present in infected mice after 1 year of age. We further confirm the presence of B. burgdorferi in the tail through quantification of bioluminescence and immunohistochemistry of both C3H/HeJ and C57BL/6J mice. This relationship among Lyme disease, atopic dermatitis, and host age seen in the mouse model is consistent with a large pool (342,499) of human epidemiological data from Finland. We identified 5,248 individuals with Lyme disease and 17,233 with atopic dermatitis in FinnGen. Retrospective analysis shows Lyme disease is associated with atopic dermatitis (OR = 1.91 [1.68 -2.37], P < 2e-16). More visits due to Lyme disease complications (3 or more visits versus 1 visit) were associated with atopic dermatitis (OR = 2.19 [1.35-3.55], P = 0.0014) and risk of developing atopic dermatitis over time (HR=2.26 [1.54-3.95], P = 0.0017). Data from mice and humans reveal a novel relationship among Lyme disease, age, and atopic dermatitis. Through defined pathological scoring, we demonstrate the onset of murine atopic dermatitis with B. burgdorferi infection, which is further exacerbated by host age at time of infection. In humans, a diagnosis of Lyme disease in FinnGen was associated with atopic dermatitis and further research is warranted to establish causation.

immunology↗

bioRxiv2022

Cell type-specific aging clocks to quantify aging and rejuvenation in regenerative regions of the brain

Aging manifests as progressive dysfunction culminating in death. The diversity of cell types is a challenge to the precise quantification of aging and its reversal. Here we develop a suite of aging clocks based on single cell transcriptomic data to characterize cell type-specific aging and rejuvenation strategies. The subventricular zone (SVZ) neurogenic region contains many cell types and provides an excellent system to study cell-level tissue aging and regeneration. We generated 21,458 single-cell transcriptomes from the neurogenic regions of 28 mice, tiling ages from young to old. With these data, we trained a suite of single cell-based regression models (aging clocks) to predict both chronological age (passage of time) and biological age (fitness, in this case the proliferative capacity of the neurogenic region). Both types of clocks perform well on independent cohorts of mice. Genes underlying the single cell-based aging clocks are mostly cell-type specific, but also include a few shared genes in the interferon and lipid metabolism pathways. We used these single cell-based aging clocks to measure transcriptomic rejuvenation, by generating single cell RNA-seq datasets of SVZ neurogenic regions for two interventions - heterochronic parabiosis (young blood) and exercise. Interestingly, the use of aging clocks reveals that both heterochronic parabiosis and exercise reverse transcriptomic aging in the niche, but in different ways across cell types and genes. This study represents the first development of high-resolution aging clocks from single cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.

genomics↗

bioRxiv2021

Tabula Microcebus: A transcriptomic cell atlas of mouse lemur, an emerging primate model organism

Mouse lemurs are the smallest, fastest reproducing, and among the most abundant primates, and an emerging model organism for primate biology, behavior, health and conservation. Although much has been learned about their physiology and their Madagascar ecology and phylogeny, little is known about their cellular and molecular biology. Here we used droplet- and plate-based single cell RNA-sequencing to profile 226,000 cells from 27 mouse lemur organs and tissues opportunistically procured from four donors clinically and histologically characterized. Using computational cell clustering, integration, and expert cell annotation, we defined and biologically organized over 750 mouse lemur molecular cell types and their full gene expression profiles. These include cognates of most classical human cell types, including stem and progenitor cells, and the developmental programs for spermatogenesis, hematopoiesis, and other adult tissues. We also described dozens of previously unidentified or sparsely characterized cell types and subtypes. We globally compared cell type expression profiles to define the molecular relationships of cell types across the body, and explored primate cell and gene expression evolution by comparing mouse lemur cell transcriptomes to those of human, mouse, and macaque. This revealed cell type specific patterns of primate specialization, as well as many cell types and genes for which lemur provides a better human model than mouse. The atlas provides a cellular and molecular foundation for studying this primate model organism, and establishes a general approach for other emerging model organisms.

genetics↗

bioRxiv2021

Revealing conserved mechanisms of neurodegeneration in a colonial chordate

Loss of the brains functional ability is a common symptom of aging and neurodegenerative diseases1,2. While the genetic and molecular mechanisms underlying human neurodegeneration are studied in-depth3-6, very little is known about the evolutionary origin of these traits and their involvement in loss of nervous system function in aged invertebrate species. Here we study evolutionarily conserved elements of brain degeneration using the colonial chordate model species Botryllus schlosseri. B. schlosseri reproduces both sexually and asexually7, with adult brains regenerating and degenerating multiple times throughout its adult life. Combining microscopy, transcriptomics and behavioral assays, we characterized adult brains from diverse stages and ages. We found that the number of neurons fluctuates each week, reaching a maximum of [~]1000 cells, and thereafter decreasing while the number of immunocytes increases. Comparing the number of neurons in the adult brains of young and old colonies, we found that older brains are smaller and contain fewer cells. Both during weekly degeneration cycles and overall with age, the decrease in neuron number correlates with reduced response to stimuli and with significant changes in the expression of genes with mammalian homologs associated with neural stem cells and neurodegenerative pathways. These results suggest persistent neural stem cell activity across ages and that cellular and molecular mechanisms of neurodegeneration are evolutionary conserved between tunicates and humans.

neuroscience↗

bioRxiv2021

Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development

Most cell fate trajectories during development follow a diverging, tree-like branching pattern, but the opposite can occur when distinct progenitors contribute to the same cell type. During this convergent differentiation, it is unknown if cells "remember" their origins transcriptionally or whether this influences cell behavior. Most coronary blood vessels of the heart develop from two different progenitor sources--the endocardium (Endo) and sinus venosus (SV)--but whether transcriptional or functional differences related to origin are retained is unknown. We addressed this by combining lineage tracing with single-cell RNA sequencing (scRNAseq) in embryonic and adult mouse hearts. Shortly after coronary development begins, capillary ECs transcriptionally segregated into two states that retained progenitor-specific gene expression. Later in development, when the coronary vasculature is well-established but still remodeling, capillary Ecs again segregated into two populations, but transcriptional differences were primarily related to tissue localization rather than lineage. Specifically, ECs in the heart septum expressed genes indicative of increased local hypoxia and decreased blood flow. Adult capillary ECs were more homogeneous with respect to both lineage and location. In agreement, SV- and Endo-derived ECs in adult hearts displayed similar responses to injury. Finally, scRNAseq of developing human coronary vessels indicated that the human heart followed similar principles. Thus, over the course of development, transcriptional heterogeneity in coronary ECs is first influenced by lineage, then by location, until heterogeneity declines in the homeostatic adult heart. These results highlight the plasticity of ECs during development, and the validity of the mouse as a model for human coronary development.

developmental biology↗

bioRxiv2021

Anti-GD2 antibody disrupts GD2:Siglec-7 interactions and synergizes with CD47 blockade to mediate tumor eradication

The disialoganglioside GD2 is consistently overexpressed in neuroblastoma and osteosarcoma, and is variably expressed in other sarcomas, gliomas, neuroendocrine tumors, and epithelial cancers. Anti-GD2 antibodies have improved the survival rates of patients with neuroblastoma only when administered as part of intense chemotherapy-based cytotoxic regimens, which are associated with debilitating late effects including hearing loss, growth retardation, and secondary leukemias. Despite broad expression of GD2 on osteosarcoma, anti-GD2 antibody has not mediated significant antitumor activity in that disease or any other GD2+ cancers. CD47 is a checkpoint molecule overexpressed on tumor cells that inhibits macrophage activity, and CD47 blockade has demonstrated promising clinical activity in early human trials. We investigated whether anti-CD47 antibody could enhance the efficacy of anti-GD2 antibody in neuroblastoma and other GD2+ malignancies. We demonstrate substantial synergy of these two agents, resulting in the recruitment of tumor associated macrophages (TAMs) to mediate robust and durable anti-tumor responses. The responses are driven by GD2-specific factors that reorient the balance of macrophage activity towards phagocytosis of tumor cells, including disruption of a newly described GD2:Siglec-7 axis. These results demonstrate the unique synergy of combining anti-GD2 with anti-CD47, which has the potential to significantly enhance outcomes for children with neuroblastoma and osteosarcoma and will soon be investigated in a first-in-human clinical trial.

immunology↗

bioRxiv2020

Global Age-Specific Patterns of Cyclic Gene Expression Revealed by Tunicate Transcriptome Atlas

Expression levels of circadian clock genes, which regulate 24-hour rhythms of behavior and physiology, have been shown to change with age. However, a study holistically linking aging and circadian gene expression is missing. Using the colonial chordate Botryllus schlosseri, we combined transcriptome sequencing and stem cell-mediated aging phenomena to test how circadian gene expression changes with age. This revealed that B. schlosseri clock and clock-controlled genes oscillate organism-wide, with daily, age-specific amplitudes and frequencies. These age-related, circadian patterns persist at the tissue level, where dramatic variations in cyclic gene expression of tissue profiles link to morphological and cellular aging phenotypes. Similar cyclical expression differences were found in hundreds of pathways associated with known hallmarks of aging, as well as pathways that were not previously linked to aging. The atlas we developed points to alterations in circadian gene expression as a key regulator of aging. One Sentence SummaryThe Ticking Clock: Systemic changes in circadian gene expression correlates with wide-ranging phenotypes of aging

developmental biology↗

bioRxiv2019

Mass spectrometry analysis of mouse hematopoietic stem cells and their progenitors reveals differential expression within and between proteome and transcriptome throughout adult and aged hematopoiesis

SummaryHematopoietic stem cells (HSCs) are responsible for the generation of blood and immune cells throughout life. They have the unique ability to self-renew and generate more HSCs or differentiate into a progenitor cell in response to cell-intrinsic and -extrinsic stimuli. The balance of HSC fate commitment is critical for a healthy blood supply. Imbalances during hematopoiesis, which are frequent in aging, can result in hematological malignancies and pre-malignancies as well as increase risk of atherosclerosis. Given the importance of HSCs and their progenitors, they have been extensively characterized in genomic and transcriptomic studies. However, an understanding of protein expression within the HSC compartment and more broadly throughout hematopoiesis remains poorly understood, and it has been widely reported that the correlation between mRNA and proteins is more complicated than previously thought. Previous mouse mass spectrometry studies have focused either specifically on stem and the first early progenitor or broadly across mixed populations of stem and progenitor cells, which do not allow for cell-type specific protein resolution across stages of differentiation. Mass cytometry has been employed to characterize transcription factor expression in human HSCs and progenitors but does not apply an unbiased discovery approach. New mass spectrometry technology now allows for deep proteomic coverage with no more than 200 ng of sample input. We report here a proteomics resource characterizing protein expression in mouse adult and aged HSCs, multipotent progenitors and oligopotent progenitors, 12 cell types in total. We validated differential expression by flow cytometry analysis and immunofluorescence staining. Additionally, we investigated the relationship between mRNA and protein levels of individual genes in HSCs compared to progenitors through RNA sequencing studies and identified two proteins that appear to be uniquely regulated in the HSC compartment, Cpin1 and Adnp. In summary, this resource provides proteomic coverage of adult and aged hematopoietic stem cells and their progenitors and reveals changes in protein abundance between cell types, with potential future implications in understanding mechanisms for stem-cell maintenance, niche interactions and fate determination.

cell biology↗

bioRxiv2019

Overexpression of CD47 is associated with brain overgrowth in 16p11.2 deletion syndrome

One of the most common genetic linkages associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, occurs at the 16p11.2 locus. Copy number variants (CNVs) of the 16p gene can manifest in opposing head sizes. 16p11.2 deletion carriers tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a dont eat me signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis both in vitro and in vivo. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. Furthermore, 16p11.2 deletion NPCs and OPCs upregulate cell surface expression of calreticulin (a pro-phagocytic eat me signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. While the CD47 pathway is commonly implicated in cancer progression, we document a novel role for CD47 in regulating brain overgrowth in psychiatric disorders and identify new targets for therapeutic intervention.

neuroscience↗

bioRxiv2019

Molecular and Morphological Signatures of Chordate Development: Two Distinct Pathways, One Tunicate

All chordates, including urochordates such as tunicates, develop through embryogenesis. The chordate larvae of colonial tunicates metamorphose to lose all chordate structures such as notochord, neural tube, segmented musculature, and then develop by asexual reproduction [blastogenesis], whereby stem cells form tissues and organs. These two developmental pathways establish the same body axis, morphogenetic patterning and organ formation. It is unknown if this convergent morphology implies convergent cellular and molecular mechanisms, and whether the stem cells that mediate these processes differ. Using the colonial tunicate Botryllus schlosseri, we combined transcriptome sequencing and multiple microscopy techniques to study the molecular and morphological signatures of cells at each developmental stage of embryogenesis and blastogenesis. This revealed that the molecular programs are distinct, but the blastogenic tissue-specific stem cells and embryonic precursor populations share similar molecular profiles. By comparing embryogenesis in other chordates we found shared developmental principles, highlighting transcription factors as key evolutionary conserved elements. This study establishes a platform for advancing the science of stem cell biology and regulation of development and regeneration.

developmental biology↗

bioRxiv2019

A molecular cell atlas of the human lung from single cell RNA sequencing

Although single cell RNA sequencing studies have begun providing compendia of cell expression profiles, it has proven more difficult to systematically identify and localize all molecular cell types in individual organs to create a full molecular cell atlas. Here we describe droplet- and plate-based single cell RNA sequencing applied to [~]75,000 human lung and blood cells, combined with a multi-pronged cell annotation approach, which have allowed us to define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 of 45 previously known cell types or subtypes and 14 new ones. This comprehensive molecular atlas elucidates the biochemical functions of lung cell types and the cell-selective transcription factors and optimal markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signaling interactions including sources and targets of chemokines in immune cell trafficking and expression changes on lung homing; and identifies the cell types directly affected by lung disease genes and respiratory viruses. Comparison to mouse identified 17 molecular types that appear to have been gained or lost during lung evolution and others whose expression profiles have been substantially altered, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions, and interactions are achieved in development and tissue engineering and altered in disease and evolution.

genomics↗

bioRxiv2019

Neogenin-1 distinguishes between myeloid-biased and balanced Hoxb5+ long-term hematopoietic stem cells

Hematopoietic stem cells (HSCs) self-renew and generate all blood cells. Recent studies with single-cell transplants (1-3) and lineage tracing (4, 5) suggest that adult HSCs are diverse in their reconstitution and lineage potentials. However, prospective isolation of these subpopulations has remained challenging. Here, we identify Neogenin-1 (NEO1) as a unique surface marker on a fraction of mouse HSCs labeled with Hoxb5, a specific reporter of long-term HSCs (LT-HSCs) (6). We show that NEO1+Hoxb5+ LT-HSCs expand with age and respond to myeloablative stress, while NEO1-Hoxb5+ LT-HSCs exhibit no significant change in number. NEO1+Hoxb5+ LT-HSCs are more often in the G2/S cell cycle phase compared to NEO1-Hoxb5+ LT-HSCs in both young and old bone marrow. Upon serial transplantation, NEO1+Hoxb5+ LT-HSCs exhibit myeloid-biased differentiation and reduced reconstitution, while NEO1-Hoxb5+ LT-HSCs are lineage-balanced and stably reconstitute recipients. Gene expression comparison reveals increased expression of cell cycle genes and evidence of lineage-priming in the NEO1+ fraction. Finally, transplanted NEO1+Hoxb5+ LT-HSCs rarely generate NEO1-Hoxb5+ LT-HSCs, while NEO1-Hoxb5+ LT-HSCs repopulate both LT-HSC fractions. This supports a model in which dormant, balanced, NEO1-Hoxb5+ LT-HSCs can hierarchically precede active, myeloid-biased NEO1+Hoxb5+ LT-HSCs.\n\nSIGNIFICANCE STATEMENTHematopoietic stem cells (HSCs) are rare cells that have the unique ability to regenerate themselves and produce all blood cells throughout life. However, HSCs are functionally heterogeneous and several studies have shown that HSCs can differ in their contribution to major blood lineages. In this study, we discovered that the surface marker, Neogenin-1, can divide mouse HSCs into two subpopulations--one that is more active but biased towards producing myeloid cells and another that is more dormant and capable of equally producing all blood lineages. Neogenin-1 reveals the diversity and hierarchical relationship of HSCs in the mouse bone marrow, enables the prospective isolation of myeloid-biased and balanced HSCs, and opens opportunities to do the same in humans.

cell biology↗

bioRxiv2018

Heme oxygenase-1 deficiency affects bone marrow niche and triggers premature exhaustion of hematopoietic stem cells.

While intrinsic changes in aging hematopoietic stem cells (HSCs) are well-characterized, it remains unclear how hematopoietic niche affects HSC aging. Here, we demonstrate that cells in the niche -- endothelial cells (ECs) and CXCL12-abundant reticular cells (CARs) -- highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. RNA-sequencing shows that ECs and CARs from HO-1-deficient animals (HO-1-/-) produce less hematopoietic factors. Consequently, HSCs from young HO-1-/- animals lose quiescence and regenerative potential. Young HO-1-/- HSCs exhibit features of premature aging on the transcriptional and functional level. HO-1+/+ HSCs transplanted into HO-1-/- recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1-/- HSCs to the HO-1+/+ recipients recovers the regenerative potential of HO-1-/- HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature aging and may restore the function of aged HSCs.

cell biology↗

bioRxiv2018

Clonal Level Lineage Commitment Pathways of Hematopoietic Stem Cells In Vivo

While hematopoietic stem cells (HSCs) have been extensively studied at the population level, little is known about the lineage commitment of individual clones. Here, we provide comprehensive maps of in vivo HSC clonal development in mice under homeostasis and after depletion of the endogenous hematopoietic system. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the hematopoietic system has been depleted by irradiation or by an anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiates while dominantly expanding and exhibiting lineage bias. We identified the cellular origins of clonal dominance and lineage bias, and uncovered the lineage commitment pathways that lead HSC clones to differential blood production. This study reveals surprising alterations in HSC regulation by irradiation, and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.\n\nSIGNIFICANCE STATEMENTHematopoietic stem cells (HSCs) sustain daily blood production through a complex step-wise lineage commitment process. In this work, we present the first comprehensive study of HSC lineage commitment at the clonal level and identify new HSC regulatory mechanisms that are undetectable by conventional population level studies. First, we uncover distinct HSC clonal pathways that lead to differential blood production and imbalances. Second, we reveal that HSC regulation under physiological conditions is strikingly different from that after injury. Third, we present a comprehensive map of HSC activities in vivo at the clonal level.

systems biology↗