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Myelodysplastic syndrome (MDS) are clonal haematopoietic stem cell (HSC) disorders driven by a complex combination(s) of changes within the genome that result in heterogeneity in both clinical phenotype and disease outcomes. MDS is among the most common of the haematological cancers and its incidence markedly increases with age. Currently available treatments have limited success, with <5% of patients undergoing allogeneic HSC transplantation, a procedure that offers the only possible cure. Critical contributions of the bone marrow microenvironment to the MDS have recently been investigated. Although the better understanding of the underlying biology, particularly genetics of haematopoietic stem cells, has led to better disease and risk classification; however, the role that the bone marrow microenvironment plays in the development of MDS remains largely unclear. This review provides a comprehensive overview of the latest developments in understanding the aetiology of MDS, particularly focussing on understanding how HSCs and the surrounding immune/non-immune bone marrow niche interacts together.

There has been an escalation in reports over the last decade examining the efficacy of bone marrow derived mesenchymal stem/stromal cells (BMSC) in bone tissue engineering and regenerative medicine-based applications. The multipotent differentiation potential, myelosupportive capacity, anti-inflammatory and immune-modulatory properties of BMSC underpins their versatile nature as therapeutic agents. This review addresses the current limitations and challenges of exogenous autologous and allogeneic BMSC based regenerative skeletal therapies in combination with bioactive molecules, cellular derivatives, genetic manipulation, biocompatible hydrogels, solid and composite scaffolds. The review highlights the current approaches and recent developments in utilizing endogenous BMSC activation or exogenous BMSC for the repair of long bone and vertebrae fractures due to osteoporosis or trauma. Current advances employing BMSC based therapies for bone regeneration of craniofacial defects is also discussed. Moreover, this review discusses the latest developments utilizing BMSC therapies in the preclinical and clinical settings, including the treatment of bone related diseases such as Osteogenesis Imperfecta.

Chronic myeloid leukemia (CML) has been a “model disease” with a long history. Beginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here the journey of CML, focusing on molecular pathways relating to signaling, metabolism and the bone marrow microenvironment. We highlight current strategies for combination therapies aimed at eradicating the CML stem cell; hopefully the final destination of this long voyage.

Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. 4fLEX7tLHnLn8Cp1swJnhp Video Abstract

Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.

Extensive research has explored the functional correlation between stem cells and progenitor cells, particularly in blood. Hematopoietic stem cells (HSCs) can self-renew and regenerate tissues within the bone marrow, while stromal cells regulate tissue function. Recent studies have validated the role of mammalian stem cells within specific environments, providing initial empirical proof of this functional phenomenon. The interaction between bone and blood has always been vital to the function of the human body. It was initially proposed that during evolution, mammalian stem cells formed a complex relationship with the surrounding microenvironment, known as the niche. Researchers are currently debating the significance of molecular-level data to identify individual stromal cell types due to incomplete stromal cell mapping. Obtaining these data can help determine the specific activities of HSCs in bone marrow. This review summarizes key topics from previous studies on HSCs and their environment, discussing current and developing concepts related to HSCs and their niche in the bone marrow.

Over the past two decades, the natural history of multiple myeloma (MM) has evolved dramatically, owing primarily to novel agents targeting MM in the bone marrow microenvironment (BMM) pathways. However, the mechanisms of resistance acquisition remain a mystery and are poorly understood. Autophagy and apoptosis are tightly controlled processes and play a critical role in the cell growth, development, and survival of MM. Genetic instability and abnormalities are two hallmarks of MM. During MM progression, plasma malignant cells become genetically unstable and activate various signaling pathways, resulting in the overexpression of abnormal proteins that disrupt autophagy and apoptosis biological processes. Thus, achieving a better understanding of the autophagy and apoptosis processes and the proteins that crosslinked both pathways, could provide new insights for the MM treatment and improve the development of novel therapeutic strategies to overcome resistance. This review presents a sufficient overview of the roles of autophagy and apoptosis and how they crosslink and control MM progression and drug resistance. Potential combination targeting of both pathways for improving outcomes in MM patients also has been addressed.

Research in the last decade has shown that hematopoietic stem cells (HSCs) interact with and are modulated by a complex multicellular microenvironment in the bone marrow, which includes both the HSC progeny and multiple non-hematopoietic cell types. Intense work is gradually throwing light on the composition of the HSC niche and the molecular cues exchanged between its components, which has implications for HSC production, maintenance and expansion. In addition, it has become apparent that bidirectional interactions between leukemic cells and their niche play a previously unrecognized role in the initiation and development of hematological malignancies. Consequently, targeting of the malignant niche holds considerable promise for more specific antileukemic therapies. Here we summarize the latest insights into HSC niche biology and recent work showing multiple connections between hematological malignancy and alterations in the bone marrow microenvironment.

Prostate cancer (PCa) continues to be the most common, noncutaneous cancer in men. Bone is the most frequent site of PCa metastases, and up to 90% of patients with advanced PCa develop bone metastases. An altered bone marrow microenvironment, induced by obesity, is a significant mediator for the bone tropism of PCa. However, the specific molecular mechanisms by which obesity causes changes in the bone marrow microenvironment, leading to PCa bone metastasis, are not fully understood. Our results demonstrate that a high‐fat diet (HFD) leads to dyslipidemia and changes in bone marrow of nude mice: an increase in the area and number of adipocytes and a reduction in the area and number of osteoblasts. Moreover, a HFD promoted cyclooxygenase 2 (COX2) expression and inhibited osteoprotegerin (OPG) expression in the bone microenvironment. Additionally, the total level of free fatty acids (FFAs) and caprylic acid (C8:0) was significantly higher in PCa patients with bone metastases. In vitro, caprylic acid (C8:0) promoted bone mesenchymal stem cell (MSC)‐derived adipocytic differentiation, COX2 expression, and prostaglandin E2 (PGE2) secretion, whereas osteoblastic differentiation and OPG expression were reduced. Furthermore, caprylic acid (C8:0)‐treated adipocytes promoted the invasion and migration of PCa cells. Taken together, our findings suggest caprylic acid (C8:0) promotes bone metastasis of PCa by dysregulated adipo‐osteogenic balance of bone marrow. Obesity‐induced high level of free fatty acids could change the bone marrow microenvironment that provides \"fertile soil\" for bone metastasis of prostate cancer. It was found for the first time that increased caprylic acid (C8:0) could promote the area and number of adipocytes and the level of cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) in the bone marrow cavity, which causes prostate cancer bone metastasis.

The bone marrow microenvironment (BMM) plays a crucial role in the pathogenesis and progression of acute myeloid leukemia (AML). AML cells can modify the BMM to establish a more favorable environment for their survival. However, the mechanism about the complex regulatory interplay between the BMM and AML cells remains unclear. In this study, we used proteomic analysis to elucidate the potential mechanisms underlying the interaction between bone marrow stromal cells (BMSCs) and AML cells. We found that the co-culture of AML cells and BMSCs facilitated the proliferation of AML cells, suppressed the proliferation of BMSCs and triggered their senescence. Furthermore, we show the aberrant expression of S100A8 that plays a crucial role in the communication between AML cells and BMSCs. In the co-culture system, overexpression of S100A8 in AML cells activated NOX2 and induced the production of reactive oxygen species (ROS) in the supernatant, thereby suppressing the proliferation of BMSCs and facilitating the senescence of BMSCs. Subsequently, aging BMSCs secreted a variety of cytokines, including IL-6, CXCL5, MIP-1b, etc. as shown by Cytokine Array and qPCR analysis, which had stimulatory effects on the progression of AML. In conclusion, the present study reveals the crucial involvement of the S100A8-NOX2-ROS signaling pathway in mediating communication between AML cells and BMSCs, suggesting that targeting S100A8 may constitute an efficient strategy for AML therapy.