scholarly journals Targeting the Molecular and Cellular Interactions of the Bone Marrow Niche in Immunologic Disease

2014 ◽  
Vol 14 (2) ◽  
Author(s):  
Jaime M. Brozowski ◽  
Matthew J. Billard ◽  
Teresa K. Tarrant
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Niche ◽  
Cellular Interactions ◽  
Immunologic Disease

scholarly journals Therapeutic Targeting of the Leukaemia Microenvironment

2021 ◽  
Vol 22 (13) ◽  
pp. 6888
Author(s):  
Vincent Kuek ◽  
Anastasia M. Hughes ◽  
Rishi S. Kotecha ◽  
Laurence C. Cheung
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Microenvironment ◽  
Bone Marrow Niche ◽  
Cellular Interactions ◽  
Remission Rates ◽  
Leukaemic Cells ◽  
Risk Patients ◽  
Novel Strategy ◽  
Therapeutic Perspective ◽  
Survival Mechanisms

In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are common due to the survival mechanisms utilised by leukaemic cells. One such mechanism is through hijacking of the bone marrow microenvironment, where healthy haematopoietic machinery is transformed or remodelled into a hiding ground or “sanctuary” where leukaemic cells can escape chemotherapy-induced cytotoxicity. The bone marrow microenvironment, which consists of endosteal and vascular niches, can support leukaemogenesis through intercellular “crosstalk” with niche cells, including mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts. Here, we summarise the regulatory mechanisms associated with leukaemia–bone marrow niche interaction and provide a comprehensive review of the key therapeutics that target CXCL12/CXCR4, Notch, Wnt/b-catenin, and hypoxia-related signalling pathways within the leukaemic niches and agents involved in remodelling of niche bone and vasculature. From a therapeutic perspective, targeting these cellular interactions is an exciting novel strategy for enhancing treatment efficacy, and further clinical application has significant potential to improve the outcome of patients with leukaemia.

scholarly journals Myeloproliferative Neoplasia Remodels the Endosteal Bone Marrow Niche into a Self-Reinforcing Leukemic Niche

2013 ◽  
Vol 13 (3) ◽  
pp. 285-299 ◽  
Author(s):  
Koen Schepers ◽  
Eric M. Pietras ◽  
Damien Reynaud ◽  
Johanna Flach ◽  
Mikhail Binnewies ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Niche

scholarly journals Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 68
Author(s):  
Fulvio Massaro ◽  
Florent Corrillon ◽  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Laurence Lagneaux ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cell Communication ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Major Player

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

scholarly journals Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie-Theresa Weickert ◽  
Judith S. Hecker ◽  
Michèle C. Buck ◽  
Christina Schreck ◽  
Jennifer Rivière ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Fate ◽  
Stromal Cells ◽  
Adipogenic Differentiation ◽  
Cell Types ◽  
Bone Marrow Niche ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Bm Niche

AbstractMyelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.

3036 – BONE MARROW TRANSPLANTATION COMPROMISES THE REGENERATIVE CAPACITY OF THE BONE MARROW NICHE

2020 ◽  
Vol 88 ◽  
pp. S49
Author(s):  
Theresa Sippenauer ◽  
J. Geuder ◽  
J. Hecker ◽  
F. Hettler ◽  
S. Romero-Marquez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Bone Marrow Niche ◽  
Regenerative Capacity

scholarly journals Sympathetic Enhancement of Memory T-Cell Homing and Hypertension Sensitization

2020 ◽  
Vol 126 (6) ◽  
pp. 708-721 ◽  
Author(s):  
Liang Xiao ◽  
Luciana Simao do Carmo ◽  
Jason D. Foss ◽  
Wei Chen ◽  
David G. Harrison
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Sympathetic Nerves ◽  
Designer Drug ◽  
Effector Memory ◽  
Bone Marrow Niche ◽  
Sympathetic Outflow ◽  
Ang Ii ◽  
Cell Homing

Rationale: Effector memory T lymphocytes (T EM cells) exacerbate hypertension in response to repeated hypertensive stimuli. These cells reside in the bone marrow for prolonged periods and can be reactivated on reexposure to the hypertensive stimulus. Objective: Because hypertension is associated with increased sympathetic outflow to the bone marrow, we hypothesized that sympathetic nerves regulate accumulation and reactivation of bone marrow–residing hypertension-specific T EM cells. Methods and Results: Using unilateral superior cervical ganglionectomy in wild-type C57BL/6 mice, we showed that sympathetic nerves create a bone marrow environment that supports residence of hypertension-specific CD8 + T cells. These cells, defined by their proliferative response on coculture with dendritic cells from Ang (angiotensin) II–infused mice, were reduced in denervated compared with innervated bone of Ang II–infused mice. Adoptively transferred CD8 + T cells from Ang II–infused mice preferentially homed to innervated compared with denervated bone. In contrast, ovalbumin responsive T cells from OT-I mice did not exhibit this preferential homing. Increasing superior cervical ganglion activity by activating Gq-coupled designer receptor exclusively activated by designer drug augmented CD8 + T EM bone marrow accumulation. Adoptive transfer studies using mice lacking β2AR (β2 adrenergic receptors) indicate that β2AR in the bone marrow niche, rather than T-cell β2AR is critical for T EM cell homing. Inhibition of global sympathetic outflow using Gi-coupled DREADD (designer receptor exclusively activated by designer drug) injected into the rostral ventrolateral medulla or treatment with a β2AR antagonist reduced hypertension-specific CD8 + T EM cells in the bone marrow and reduced the hypertensive response to a subsequent response to low dose Ang II. Conclusions: Sympathetic nerves contribute to the homing and survival of hypertension-specific T EM cells in the bone marrow after they are formed in hypertension. Inhibition of sympathetic nerve activity and β2AR blockade reduces these cells and prevents the blood pressure elevation and renal inflammation on reexposure to hypertension stimuli.

scholarly journals Bone marrow niche crosses paths with BMPs: a road to protection and persistence in CML

2019 ◽  
Vol 47 (5) ◽  
pp. 1307-1325 ◽  
Author(s):  
Caroline Busch ◽  
Helen Wheadon
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Morphogenetic Proteins ◽  
Kinase Inhibitor ◽  
Survival Rates ◽  
High Survival ◽  
Bone Marrow Niche ◽  
Matrix Deposition ◽  
Bmp Receptors ◽  
Number Of Patients

Abstract Chronic myeloid leukaemia (CML) is a paradigm of precision medicine, being one of the first cancers to be treated with targeted therapy. This has revolutionised CML therapy and patient outcome, with high survival rates. However, this now means an ever-increasing number of patients are living with the disease on life-long tyrosine kinase inhibitor (TKI) therapy, with most patients anticipated to have near normal life expectancy. Unfortunately, in a significant number of patients, TKIs are not curative. This low-level disease persistence suggests that despite a molecularly targeted therapeutic approach, there are BCR-ABL1-independent mechanisms exploited to sustain the survival of a small cell population of leukaemic stem cells (LSCs). In CML, LSCs display many features akin to haemopoietic stem cells, namely quiescence, self-renewal and the ability to produce mature progeny, this all occurs through intrinsic and extrinsic signals within the specialised microenvironment of the bone marrow (BM) niche. One important avenue of investigation in CML is how the disease highjacks the BM, thereby remodelling this microenvironment to create a niche, which enables LSC persistence and resistance to TKI treatment. In this review, we explore how changes in growth factor levels, in particular, the bone morphogenetic proteins (BMPs) and pro-inflammatory cytokines, impact on cell behaviour, extracellular matrix deposition and bone remodelling in CML. We also discuss the challenges in targeting LSCs and the potential of dual targeting using combination therapies against BMP receptors and BCR-ABL1.

scholarly journals Plasma cell dynamics in the bone marrow niche

Cell Reports ◽  
2021 ◽  
Vol 34 (6) ◽  
pp. 108733
Author(s):  
Zachary Benet ◽  
Zhixin Jing ◽  
David R. Fooksman
Keyword(s):  
Bone Marrow ◽  
Plasma Cell ◽  
Bone Marrow Niche ◽  
Cell Dynamics
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