The Bone marrow stroma in human myelodysplastic syndrome reveals alterations that regulate disease progression [Human and Mouse]
Ontology highlight
ABSTRACT: Myelodysplastic syndromes (MDS) are a heterogenous group of diseases affecting the hematopoietic stem cell that are curable only by stem cell transplantation. Both hematopoietic cell intrinsic changes and extrinsic signals from the bone marrow niche seem to ultimately lead to MDS. Animal models of MDS indicate that alterations in specific mesenchymal progenitor subsets in the bone marrow microenvironment can induce or select for abnormal hematopoietic cells. Here we identify a subset of human bone marrow (BM) mesenchymal cells marked by the expression of CD271, CD146 and CD106. This subset of human mesenchymal cells is equivalent to those in mice that, when perturbed, results in an MDS-like syndrome. Transcriptional analysis identified epithelial to mesenchymal transition as the most enriched gene set and Osteopontin (SPP1) as the most overexpressed gene. The loss of expression of Spp1 in the microenvironment resulted in an accelerated progression of the transplanted Vav-driven Nup98-HoxD13 MDS model as demonstrated by increased chimerism, increased contribution of mutant cells to the myeloid lineage and a more pronounced anemia when compared to animals with a wild type microenvironment. These data indicate that molecular perturbations can occur in specific bone marrow mesenchymal subsets of MDS patients. However, the niche adaptations to dysplastic clones include Spp1 overexpression that can constrain disease progression. Therefore, niche changes with malignant disease can also serve to protect the host.
Project description:Myelodysplastic syndromes (MDS) are a heterogenous group of diseases affecting the hematopoietic stem cell that are curable only by stem cell transplantation. Both hematopoietic cell intrinsic changes and extrinsic signals from the bone marrow niche seem to ultimately lead to MDS. Animal models of MDS indicate that alterations in specific mesenchymal progenitor subsets in the bone marrow microenvironment can induce or select for abnormal hematopoietic cells. Here we identify a subset of human bone marrow (BM) mesenchymal cells marked by the expression of CD271, CD146 and CD106. This subset of human mesenchymal cells is equivalent to those in mice that, when perturbed, results in an MDS-like syndrome. Transcriptional analysis identified epithelial to mesenchymal transition as the most enriched gene set and Osteopontin (SPP1) as the most overexpressed gene. The loss of expression of Spp1 in the microenvironment resulted in an accelerated progression of the transplanted Vav-driven Nup98-HoxD13 MDS model as demonstrated by increased chimerism, increased contribution of mutant cells to the myeloid lineage and a more pronounced anemia when compared to animals with a wild type microenvironment. These data indicate that molecular perturbations can occur in specific bone marrow mesenchymal subsets of MDS patients. However, the niche adaptations to dysplastic clones include Spp1 overexpression that can constrain disease progression. Therefore, niche changes with malignant disease can also serve to protect the host.
Project description:Myelodysplastic syndromes (MDS) are a heterogenous group of diseases affecting the hematopoietic stem cell that are curable only by stem cell transplantation. Both hematopoietic cell intrinsic changes and extrinsic signals from the bone marrow niche seem to ultimately lead to MDS. Animal models of MDS indicate that alterations in specific mesenchymal progenitor subsets in the bone marrow microenvironment can induce or select for abnormal hematopoietic cells. Here we identify a subset of human bone marrow (BM) mesenchymal cells marked by the expression of CD271, CD146 and CD106. This subset of human mesenchymal cells is equivalent to those in mice that, when perturbed, results in an MDS-like syndrome. Transcriptional analysis identified epithelial to mesenchymal transition as the most enriched gene set and Osteopontin (SPP1) as the most overexpressed gene. The loss of expression of Spp1 in the microenvironment resulted in an accelerated progression of the transplanted Vav-driven Nup98-HoxD13 MDS model as demonstrated by increased chimerism, increased contribution of mutant cells to the myeloid lineage and a more pronounced anemia when compared to animals with a wild type microenvironment. These data indicate that molecular perturbations can occur in specific bone marrow mesenchymal subsets of MDS patients. However, the niche adaptations to dysplastic clones include Spp1 overexpression that can constrain disease progression. Therefore, niche changes with malignant disease can also serve to protect the host.
Project description:The bone marrow provides the niche microenvironment for the long-term maintenance of various cell types, such as hematopoietic stem cells (HSC) or long-lived plasma cells (LLPC). The maintenance of HSC and LLPC relies on specific niches composed of specific soluble molecules, adhesion molecules, and proteins of the extracellular matrix, which are partly provided by mesenchymal stromal cells. In recent years, there have been many efforts to simulate the niche situation in vitro by the generation of organ and tissue surrogates by organoid technology. In this study, we cultured bone marrow-derived human mesenchymal stromal cells on a 3D scaffold to emulate the niche microenvironment by generating a bone marrow organoid. Transcriptional analysis of differentially expressed genes and the general expression pattern of bone marrow-relevant genes in 3D demonstrate the eligibility of the 3D culture system for the maintenance of bone marrow-associated HSC and LLPC.
Project description:The paper describes a model of tumor invasion to bone marrow.
Created by COPASI 4.26 (Build 213)
This model is described in the article:
Modeling invasion of metastasizing cancer cells to bone marrow utilizing ecological principles
Kun-Wan Chen, Kenneth J Pienta
Theoretical Biology and Medical Modelling 2011, 8:36
Abstract:
Background: The invasion of a new species into an established ecosystem can be directly compared to the steps involved in cancer metastasis. Cancer must grow in a primary site, extravasate and survive in the circulation to then intravasate into target organ (invasive species survival in transport). Cancer cells often lay dormant at their metastatic site for a long period of time (lag period for invasive species) before proliferating (invasive spread). Proliferation in the new site has an impact on the target organ microenvironment (ecological impact) and eventually the human host (biosphere impact).
Results: Tilman has described mathematical equations for the competition between invasive species in a structured habitat. These equations were adapted to study the invasion of cancer cells into the bone marrow microenvironment as a structured habitat. A large proportion of solid tumor metastases are bone metastases, known to usurp hematopoietic stem cells (HSC) homing pathways to establish footholds in the bone marrow. This required accounting for the fact that this is the natural home of hematopoietic stem cells and that they already occupy this structured space. The adapted Tilman model of invasion dynamics is especially valuable for modeling the lag period or dormancy of cancer cells.
Conclusions: The Tilman equations for modeling the invasion of two species into a defined space have been modified to study the invasion of cancer cells into the bone marrow microenvironment. These modified equations allow a more flexible way to model the space competition between the two cell species. The ability to model initial density, metastatic seeding into the bone marrow and growth once the cells are present, and movement of cells out of the bone marrow niche and apoptosis of cells are all aspects of the adapted equations. These equations are currently being applied to clinical data sets for verification and further refinement of the models.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models .
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide.
Please refer to CC0 Public Domain Dedication for more information.
Project description:The paper describes a model of tumor invasion to bone marrow.
Created by COPASI 4.26 (Build 213)
This model is described in the article:
Modeling invasion of metastasizing cancer cells to bone marrow utilizing ecological principles
Kun-Wan Chen, Kenneth J Pienta
Theoretical Biology and Medical Modelling 2011, 8:36
Abstract:
Background: The invasion of a new species into an established ecosystem can be directly compared to the steps involved in cancer metastasis. Cancer must grow in a primary site, extravasate and survive in the circulation to then intravasate into target organ (invasive species survival in transport). Cancer cells often lay dormant at their metastatic site for a long period of time (lag period for invasive species) before proliferating (invasive spread). Proliferation in the new site has an impact on the target organ microenvironment (ecological impact) and eventually the human host (biosphere impact).
Results: Tilman has described mathematical equations for the competition between invasive species in a structured habitat. These equations were adapted to study the invasion of cancer cells into the bone marrow microenvironment as a structured habitat. A large proportion of solid tumor metastases are bone metastases, known to usurp hematopoietic stem cells (HSC) homing pathways to establish footholds in the bone marrow. This required accounting for the fact that this is the natural home of hematopoietic stem cells and that they already occupy this structured space. The adapted Tilman model of invasion dynamics is especially valuable for modeling the lag period or dormancy of cancer cells.
Conclusions: The Tilman equations for modeling the invasion of two species into a defined space have been modified to study the invasion of cancer cells into the bone marrow microenvironment. These modified equations allow a more flexible way to model the space competition between the two cell species. The ability to model initial density, metastatic seeding into the bone marrow and growth once the cells are present, and movement of cells out of the bone marrow niche and apoptosis of cells are all aspects of the adapted equations. These equations are currently being applied to clinical data sets for verification and further refinement of the models.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models .
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide.
Please refer to CC0 Public Domain Dedication for more information.
Project description:Bone marrow (BM) mesenchymal stem and progenitor cells (MSPCs) are a critical constituent of the hematopoietic stem cell (HSC) niche. Previous studies have suggested that the zinc-finger epithelial-mesenchymal transition transcription factor Snai2 (also known as Slug) regulated HSCs autonomously. Here, we show that Snai2 expression in the BM is restricted to the BM stromal compartment where it regulates the HSC niche. Germline or MSPC-selective Snai2 deletion reduces the functional MSPC pool, their mesenchymal lineage output, and impairs HSC niche function during homeostasis and after stress. RNA-sequencing analysis revealed that Spp1 (osteopontin) expression is markedly upregulated in Snai2-deficient MSPCs. Genetic deletion of Spp1 in Snai2-deficient mice, rescues MSPCs’ functions. Thus, SNAI2 is a critical regulator of the transcriptional network maintaining MSPCs by the suppression of osteopontin expression.
Project description:Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm whose severity and treatment complexity is attributed to the presence of bone marrow (BM) fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neo-osteogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic cells and the osteoblastic niche is deregulated in the PMF BM microenvironment. Osteoblastic niche is well known to be an important support to regulate hematopoietic stem cell functions in bone marrow. A transcriptome analysis of bone marrow mesenchymal stem cells (BM-MSC) induced in vitro to differentiate in osteoblasts will help to understand the role of these cells in pathophysiology of PMF. Transcriptome analysis was performed on BM-MSC at J0 and J21 of in vitro osteoblastic differentiation. Agilent Whole Human Genome Oligo Microarrays were used to compare expression profiling of BM-MSCs from PMF patients and healthy donors before and after osteoblastic differentiation. Primary Myelofibrosis, mesenchymal stroma cells, bone marrow, myeloproliferative disorders
Project description:Acute myeloid leukemia remodels the bone marrow non-hematopoietic microenvironment which disrupts niche archiecture and normal hematopoiesis The precise interactions underlying this process are not well understood We used microarrays to detail the global programme of gene expression underlying the interactions between healthy mesenchymal stroma cells and normal hematopoietic progenitors/stem cells (HSPCs) and AML
Project description:The bone marrow microenvironment is composed of heterogeneous cell populations of non-hematopoietic cells with complex phenotypes and undefined trajectories of maturation. Among them, mesenchymal cells maintain the production of stromal, bone, fat and cartilage cells. Resolving these unique cellular subsets within the bone marrow remains challenging. Here, we used single-cell RNA-sequencing of non-hematopoietic bone marrow cells to define specific subpopulations. Furthermore, by combining computational prediction of the cell state hierarchy with known expression of key transcription factors, we mapped differentiation paths to the osteocyte, chondrocyte, and adipocyte lineages. Finally, we validated our findings using lineage-specific reporter strains and targeted knockdowns. Our analysis reveals differentiation hierarchies for maturing stromal cells, determines key transcription factors along these trajectories, and provides an understanding of the complexity of the bone marrow microenvironment.
Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms with defects in hematopoietic stem/progenitor cells (HSPCs) and possibly the HSPC niche. Here we show that patient-derived mesenchymal stromal cells (MDS MSCs) display a disturbed differentiation program and are essential for the propagation of MDS-initiating lin-CD34+CD38- stem cells in orthotopic xenografts. Overproduction of niche factors such as N-Cadherin, IGFBP2, VEGFA and LIF is associated with the ability of MDS MSCs to enhance MDS expansion. These factors represent putative therapeutic targets to disrupt critical hematopoietic-stromal interactions in MDS. Finally, healthy MSCs adopt "MDS-MSC like" molecular features when exposed to hematopoietic MDS cells, indicative of an instructive remodeling of their microenvironment. This patient-derived xenograft model therefore provides functional and molecular evidence that MDS is a complex disease involving both the hematopoietic and stromal compartments. The resulting deregulated expression of niche factors may well also be a feature of other hematopoietic malignancies.