Differentiation Of Hematopoietic Cells Research Articles

Single-chain nanobody inhibition of Notch and avidity enhancement utilizing the β-pore forming toxin Aerolysin.

Notch plays critical roles in developmental processes and disease pathogenesis, which has led to numerous efforts to modulate its function with small molecules and antibodies. Here we present a nanobody inhibitor of Notch signaling, derived from a synthetic phage-display library targeting the notch Negative Regulatory Region (NRR). The nanobody inhibits Notch signaling in a luciferase reporter assay and in Notch-dependent hematopoietic progenitor cell differentiation assay, despite a modest 19uM affinity for Notch. We addressed the low affinity by fusion to a membrane-associating domain derived from the β-Pore forming toxin Aerolysin, resulting in a significantly improved IC50 for Notch inhibition. The nanobody-aerolysin fusion inhibits proliferation of T-ALL cell lines with similar efficacy to other Notch pathway inhibitors. Overall, this study reports the development of a Notch inhibitory antibody, and demonstrates a proof-of-concept for a generalizable strategy to increase the efficacy and potency of low-affinity antibody binders.

Maternal NO2 exposure and fetal growth restriction: Hypoxia transmission and lncRNAs-proinflammation-mediated abnormal hematopoiesis

Epidemiological studies show a strong correlation between air pollution and fetal growth restriction (FGR), but existing results are controversial due to inherent limitations, such as causality of specific pollutants, developmental origin, and maternal-fetal transmission. To address this controversy, we first conducted a retrospective analysis of 28,796 newborns and revealed that maternal nitrogen dioxide (NO2) exposure during the second trimester was positively associated with FGR, with an adjusted odds ratio of 1.075 (95% confidence interval: 1.020-1.133) per 10 μg/m3 NO2 increase for small for gestational age. Then, by establishing an animal model of prenatal NO2 exposure, we confirmed its adverse effects on embryonic growth and hematopoiesis in the yolk sac and fetal liver, primarily affecting the differentiation of hematopoietic stem and progenitor cells and erythroid maturation. By applying internal exposure analyses coupled with 15N isotope tracing, we found that maternal NO2 inhalation induced acquired methemoglobinemia through its byproducts and placental hypoxia in pregnant mice. Importantly, by combining transcriptional profiling, bioinformatics analysis, and RNA binding protein immunoprecipitation (RIP)/chromatin immunoprecipitation (CHIP), we clarified that placental-fetal hypoxia transmission activated hypoxia-inducible factors, disturbed hematopoiesis through the hypoxia-inducible factor 1β-long noncoding RNAs-CCAAT/enhancer binding protein alpha-proinflammatory signaling pathway, ultimately contributing to FGR progression. These findings provide insights for risk prevention and clinical intervention to promote child well-being in NO2-polluted areas.

Identification of Biomarkers and Mechanisms Associated with Apoptosis in Recurrent Pregnancy Loss.

In this study, we employed bioinformatics techniques to identify genes associated with apoptosis in recurrent pregnancy loss (RPL). We retrieved the RPL expression profile datasets GSE165004 and GSE73025 from the Gene Expression Omnibus (GEO) database. We also obtained data from the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway of Apoptosis (hsa04210) to identify apoptosis-related genes. In addition, we performed Friends analysis to explore the interactions between differential apoptosis genes and other genes in the functional pathway. We identified six differentially expressed genes related to apoptosis, including CTSZ, BCL2, PIK3CD, KRAS, GADD45G, and CASP8, with GADD45G as the most gene. Functional fertility analysis revealed that differentially expressed genes primarily regulated protein stability, cell number homeostasis, myeloid cell homeostasis, hematopoietic progenitor cell differentiation, lytic vacuole and lysosome functions, vacuolar and lysosomal membranes, transmembrane transporter binding, protein domain-specific binding, G-protein beta-subunit binding, phospholipid binding, and were involved in pathways such as Rap1 signaling, regulation of actin cytoskeleton, and NOD-like receptor signaling. KRAS exhibited the highest mutation rate in RPL-related cancer CESC. There was also a positive correlation between differentially expressed genes and B cell memory, CD4 memory resting T cells, follicular helper T cells, naïve B cells, and resting dendritic cells. We identified six differentially expressed genes related to apoptosis in RPL, with GADD45G as the most important. NOD-like receptor signaling pathway and regulation of actin cytoskeleton could be therapeutic targets for RPL.

The Role of SIRT1 in Leukemia.

Leukemia is a type of hematological malignancy (HM) caused by uncontrolled proliferation, apoptosis, and differentiation of hematopoietic stem cells (HSCs). Leukemia cells proliferate greatly in the bone marrow (BM), infiltrate other tissues and organs, and affect the normal hematopoietic function. Although the emergence of new targeted agents and immune agents has improved the prognosis of patients, due to the complex pathogenic factors and heterogeneity of leukemia, there are still some patients with poor prognosis. Recent studies have shown that silent information regulator 1 (SIRT1) is involved in the proliferation, apoptosis, metabolism, and senescence of leukemia cells. As a double-edged sword in leukemia cells, SIRT1 can both promote and inhibit the growth of leukemia cells. Since its mechanism of action has not been elucidated, it is urgent to explore the regulatory mechanism of SIRT1 in leukemia. In this review, we discussed the mechanisms of SIRT1 in different aspects of leukemia, providing a theoretical basis for the treatment of patients with leukemia.

Relationship between adipocytes and hematological tumors in the bone marrow microenvironment: a literature review.

The bone marrow microenvironment is closely related to normal hematopoiesis and hematologic tumors. Adipocytes are an important part of the bone marrow microenvironment, in which they can release free fatty acids (FFAs) through lipolysis and secrete adipocytokines, etc., and participate in normal hematopoiesis, which is closely related to the occurrence and treatment of hematological tumors. In this review, we aim to discuss how bone marrow adipocytes (BMAs) can influence the proliferation, apoptosis, and chemotherapy resistance of cancer cells by reprogramming lipid metabolism and the secretion of various adipocytokines. Studies from 2000 to July 2024 were reviewed from PubMed, Springer Link, and the Web of Science using the keywords bone marrow microenvironment, adipocytes, lipid metabolism, adipocytokines, hematological tumor, cancer, and their combinations. Unreliable articles such as those that are old and have a low impact factor are excluded, and there is no restriction on language. Adipocytes can regulate the proliferation and differentiation of hematopoietic stem cells (HSCs) by secreting inflammatory factors and adipocytokines to maintain hematopoietic homeostasis. Adipocytes can also stimulate and accelerate the occurrence and progression of hematological tumors by secreting adipocytokines and mediating the reprogramming of lipid metabolism. Moreover, abundant adipocytes in bone marrow can protect tumor cells by physically blocking and/or secreting cytokines, leading to chemotherapy resistance. Therefore, the targeted inhibition of related lipid metabolism pathways and adipocytokines might be a potential therapeutic target for hematological tumors, which would be helpful to inhibit tumor growth and correct chemotherapy resistance.

Vasopressin drives aberrant myeloid differentiation of hematopoietic stem cells, contributing to depression in mice.

Psychological stress is often linked to depression and can also impact the immune system, illustrating the interconnectedness of mental health and immune function. Hematopoietic stem cells (HSCs) can directly sense neuroendocrine signals in bone marrow and play a fundamental role in the maintenance of immune homeostasis. However, it is unclear how psychological stress impacts HSCs in depression. Here, we report that neuroendocrine factor arginine vasopressin (AVP) promotes myeloid-biased HSC differentiation by activating neutrophils. AVP administration increases neutrophil and Ly6Chi monocyte production by triggering HSCs that rely on intrinsic S100A9 in mice. When stimulated with AVP, neutrophils return to the bone marrow and release interleukin 36G (IL-36G), which interacts with interleukin 1 receptor-like 2 (IL-1RL2) on HSCs to produce neutrophils with high Elane expression that infiltrate the brain and induce neuroinflammation. Together, these findings define HSCs as a relay between psychological stress and myelopoiesis and identify the IL-36G-IL-1RL2 axis as a potential target for depression therapy.

A bispecific nanosystem activates endogenous natural killer cells in the bone marrow for haematologic malignancies therapy.

Haematologic malignancies commonly arise from the bone marrow lesion, yet there are currently no effective targeted therapies against tumour cells in this location. Here we constructed a bone-marrow-targeting nanosystem, CSF@E-Hn, which is based on haematopoietic-stem-cell-derived nanovesicles adorned with gripper ligands (aPD-L1 and aNKG2D) and encapsulated with colony-stimulating factor (CSF) for the treatment of haematologic malignancies. CSF@E-Hn targets the bone marrow and, thanks to the gripper ligands, pulls together tumour cells and natural killer cells, activating the latter for specific tumour cell targeting and elimination. The therapeutic efficacy was validated in mice bearing acute myeloid leukaemia and multiple myeloma. The comprehensive assessment of the post-treatment bone marrow microenvironment revealed that the integration of CSF into a bone-marrow-targeted nanosystem promoted haematopoietic stem cell differentiation, boosted memory T cell generation and maintained bone homoeostasis, with long-term prevention of relapse. Our nanosystem represents a promising strategy for the treatment of haematologic malignancies.

Epitope prime editing shields hematopoietic cells from CD123 immunotherapy for acute myeloid leukemia

Acute myeloid leukemia (AML) is a malignant cancer characterized by abnormal differentiation of hematopoietic stem and progenitor cells (HSPCs). While chimeric antigen receptor T (CAR-T) cell immunotherapies target AML cells, they often induce severe on-target/off-tumor toxicity by attacking normal cells expressing the same antigen. Here, we used base editors (BEs) and a prime editor (PE) to modify the epitope of CD123 on HSPCs, protecting healthy cells from CAR-T-induced cytotoxicity while maintaining their normal function. Although BE effectively edits epitopes, complex bystander products are a concern. To enhance precision, we optimized prime editing, increasing the editing efficiency from 5.9% to 78.9% in HSPCs. Epitope-modified cells were resistant to CAR-T lysis while retaining normal differentiation and function. Furthermore, BE- or PE-edited HSPCs infused into humanized mice endowed myeloid lineages with selective resistance to CAR-T immunotherapy, demonstrating a proof-of-concept strategy for treating relapsed AML.

Developments of Fms-like Tyrosine Kinase 3 Inhibitors as Anticancer Agents for AML Treatment.

FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated gene in acute myeloid leukemia. As a receptor tyrosine kinase (RTK), FLT3 plays a role in the proliferation and differentiation of hematopoietic stem cells. As the most frequent molecular alteration in AML, FLT3 has drawn the attention of many researchers, and a lot of small molecule inhibitors targeting FLT3 have been intensively investigated as potential drugs for AML therapy. In this paper, PubMed and SciFinder® were used as a tool; the publications about "FLT3 inhibitor" and "Acute myeloid leukemia" were surveyed from 2014 to the present with an exclusion of those published as patents. In this study, the structural characterization and biological activities of representative FLT3 inhibitors were summarized. The major challenges and future directions for further research are discussed. Recently, numerous FLT3 inhibitors have been discovered and employed in FLT3-mutated AML treatment. In order to overcome the drug resistance caused by FLT3 mutations, screening multitargets FLT3 inhibitors has become the main research direction. In addition, the emergence of irreversible FLT3 inhibitors also provides new ideas for discovering new FLT3 inhibitors.

A novel study on CXXC5: unraveling its regulatory mechanisms in hematopoietic stem cell biology through proteomics and gene editing.

This study investigates the role of CXXC5 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) within the bone marrow microenvironment, utilizing advanced methodologies such as single-cell RNA sequencing (scRNA-seq), CRISPR-Cas9, and proteomic analysis. We employed flow cytometry to isolate HSCs from bone marrow samples, followed by scRNA-seq analysis using the 10x Genomics platform to examine cell clustering and CXXC5 expression patterns. CRISPR-Cas9 and lentiviral vectors facilitated the knockout and overexpression of CXXC5 in HSCs. The impact on HSCs was assessed through qRT-PCR, Western blot, CCK-8, CFU, and LTC-IC assays, alongside flow cytometry to measure apoptosis and cell proportions. A mouse model was also used to evaluate the effects of CXXC5 manipulation on HSC engraftment and survival rates. Our findings highlight the diversity of cell clustering and the significant role of CXXC5 in HSC regulation. Knockout experiments showed reduced proliferation and accelerated differentiation, whereas overexpression led to enhanced proliferation and delayed differentiation. Proteomic analysis identified key biological processes influenced by CXXC5, including cell proliferation, differentiation, and apoptosis. In vivo results demonstrated that CXXC5 silencing impaired HSC engraftment in a bone marrow transplantation model. CXXC5 is crucial for the regulation of HSC self-renewal and differentiation in the bone marrow microenvironment. Its manipulation presents a novel approach for enhancing HSC function and provides a potential therapeutic target for hematological diseases.

Lysosomal membrane protein TMEM106B modulates hematopoietic stem and progenitor cell proliferation and differentiation by regulating LAMP2A stability.

Hematopoietic stem and progenitor cells (HSPCs) are successfully employed for hematological transplantations, and impaired HSPC function causes hematological diseases and aging. HSPCs maintain the lifelong homeostasis of blood and immune cells through continuous self-renewal and maintenance of the multilineage differentiation potential. TMEM106B is a transmembrane protein localized on lysosomal membranes and associated with neurodegenerative and cardiovascular diseases; however, its roles in HSPCs and hematopoiesis are unknown. Here, we established tmem106bb-/- knockout (KO) zebrafish and showed that tmem106bb KO reduced the proliferation of HSPCs during definitive hematopoiesis. The differentiation potential of HSPCs to lymphoid lineage was reduced, whereas the myeloid and erythroid differentiation potentials of HPSCs were increased in tmem106bb-/- zebrafish. Similar results were obtained with morpholino knockdown of tmem106bb. Mechanistically, TMEM106B interacted with LAMP2A, the lysosomal associated membrane protein 2A, impaired LAMP2A-Cathepsin A interaction, and enhanced LAMP2A stability; tmem106bb KO or TMEM106B knockdown caused LAMP2A degradation and impairment of chaperone-mediated autophagy (CMA). Knockdown of lamp2a caused similar phenotypes to that in tmem106bb-/- zebrafish, and overexpression of lamp2a rescued the impaired phenotypes of HSPCs in tmem106bb-/- embryos. These results uncover a novel molecular mechanism for the maintenance of HSPC proliferation and differentiation through stabilizing LAMP2A via TMEM106B-LAMP2A interaction.

Cxcl10 and Cxcr3 regulate self-renewal and differentiation of hematopoietic stem cells

BackgroundThe function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood.MethodsWe established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3−/− and Cxcl10−/−) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3−/− and Cxcl10−/− stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3−/−or Cxcl10−/− recipient mice (CD45.2) and examined donor-contributed hematopoiesis.ResultsDeficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10−/− stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10−/− donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function.ConclusionsThe Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.

Gestational diabetes mellitus affects the differentiation of hematopoietic stem cells in neonatal umbilical cord blood.

There are abundant hematopoietic stem cells (HSCs) in cord blood. It is known that HSCs continue to differentiate to CLP, CMP and erythroid progenitor cells (EPC), EPC ultimately differentiated to platelets and erythrocytes. It has been reported that the proportion of HSCs in cord blood was higher than that in healthy pregnant women, so as the incidence of neonatal polycythemia in gestational diabetes mellitus (GDM) patients. We aimed to investigate whether the hyperglycemic and/or hyperinsulin environment in GDM patients has effects on the differentiation of HSCs into erythrocytes in offspring cord blood. In this study, we collected cord blood from 23 GDM patients and 52 healthy pregnant women at delivery. HSCs, CLP, CMP and EPCs in cord blood of the two groups were identified and quantified by flow cytometry. HSCs were sorted out and treated with glucose and insulin, respectively, and then, the changes of HSCs proliferation and differentiation were detected. Compared to healthy controls, HSCs, CMP and EPC numbers in cord blood from GDM group were significantly increased, while CLP cell number was decreased. The differentiation of HSCs into EPC was promoted after treatment with glucose or insulin. There were more HSCs in the cord blood of GDM group, and the differentiation of HSCs to EPCs was increased. These findings were probably caused by the high-glucose microenvironment and insulin medication in GDM patients, and the HSCs differentiation changes might be influencing factors of the high incidence of neonatal erythrocytosis in GDM patients.

Metabolic adaptation pilots the differentiation of human hematopoietic cells.

A continuous supply of energy is an essential prerequisite for survival and represents the highest priority for the cell. We hypothesize that cell differentiation is a process of optimization of energy flow in a changing environment through phenotypic adaptation. The mechanistic basis of this hypothesis is provided by the established link between core energy metabolism and epigenetic covalent modifications of chromatin. This theory predicts that early metabolic perturbations impact subsequent differentiation. To test this, we induced transient metabolic perturbations in undifferentiated human hematopoietic cells using pharmacological inhibitors targeting key metabolic reactions. We recorded changes in chromatin structure and gene expression, as well as phenotypic alterations by single-cell ATAC and RNA sequencing, time-lapse microscopy, and flow cytometry. Our observations suggest that these metabolic perturbations are shortly followed by alterations in chromatin structure, leading to changes in gene expression. We also show that these transient fluctuations alter the differentiation potential of the cells.

Effects of PM2.5 exposure on hematopoiesis and coupled immune disorder in adult male mice

Fine particulate matter, namely PM2.5, increases the risk of morbidity and mortality in various systems, including the hematopoietic and immune systems. However, there is limited experimental evidence supporting the association between PM2.5 exposure and hematopoietic outcomes as most studies focus on epidemiological data. In this study, adult male mice were exposed to PM2.5 for a long time to investigate hematopoietic toxicity. There were significant increases in red blood cells (RBC), hemoglobin (HGB), and white blood cells (WBC) in peripheral blood after 5-month real-environmental PM2.5 exposure, indicating elevated circulatory inflammation and potential hematopoietic abnormality. Moreover, we observed abnormal proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs), along with altered mRNA levels of hematopoietic genes and increased proinflammatory factors in the bone marrow (BM). Transcriptomic analysis of BM cells suggested that PM2.5 exposure activated immune responses associated with lymphocytes. Then, PM2.5 exposure via intratracheal instillation was performed for 8 weeks to verify the toxic effect. The results of the complete blood count were similar to those of real-environmental exposure, with drastic changes in the number and function of HSPCs, as well as mRNA levels of the hematopoietic genes and increased inflammatory factors in the BM being detected. Furthermore, lymphocyte subsets changed significantly in the BM and spleen, confirming immune disorder following PM2.5 exposure. In conclusion, PM2.5 interfered with the process of BM hematopoiesis by triggering inflammation and leading to immune disorder. Our study provided experimental evidence for the hematopoietic toxicity of PM2.5 and highlighted the significance of reducing air pollution.

Significance of targeting DNMT3A mutations in AML.

Acute myeloid leukemia (AML) is the most prevalent form of leukemia among adults, characterized by aggressive behavior and significant genetic diversity. Despite decades of reliance on conventional chemotherapy as the mainstay treatment, patients often struggle with achieving remission, experience rapid relapses, and have limited survival prospects. While intensified induction chemotherapy and allogeneic stem cell transplantation have enhanced patient outcomes, these benefits are largely confined to younger AML patients capable of tolerating intensive treatments. DNMT3A, a crucial enzyme responsible for establishing de novo DNA methylation, plays a pivotal role in maintaining the delicate balance between hematopoietic stem cell differentiation and self-renewal, thereby influencing gene expression programs through epigenetic regulation. DNMT3A mutations are the most frequently observed genetic abnormalities in AML, predominantly in older patients, occurring in approximately 20-30% of adult AML cases and over 30% of AML with a normal karyotype. Consequently, the molecular underpinnings and potential therapeutic targets of DNMT3A mutations in AML are currently being thoroughly investigated. This article provides a comprehensive summary and the latest insights into the structure and function of DNMT3A, examines the impact of DNMT3A mutations on the progression and prognosis of AML, and explores potential therapeutic approaches for AML patients harboring DNMT3A mutations.

Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma

AbstractHematologic toxicity is a common side effect of chimeric antigen receptor T-cell (CAR-T) therapies, being particularly severe among patients with relapsed or refractory multiple myeloma (MM). In this study, we characterized 48 patients treated with B-cell maturation antigen (BCMA) CAR-T cells to understand kinetics of cytopenia, identify predictive factors, and determine potential mechanisms underlying these toxicities. We observed that overall incidence of cytopenia was 95.7%, and grade >3 thrombocytopenia and neutropenia, 1 month after infusion, was observed in 57% and 53% of the patients, respectively, being still present after 1 year in 4 and 3 patients, respectively. Baseline cytopenia and high peak inflammatory markers were highly correlated with cytopenia that persisted up to 3 months. To determine potential mechanisms underlying cytopenias, we evaluated the paracrine effect of BCMA CAR-T cells on hematopoietic stem and progenitor cell (HSPC) differentiation using an ex vivo myeloid differentiation model. Phenotypic analysis showed that supernatants from activated CAR-T cells (spCAR) halted HSPC differentiation, promoting more immature phenotypes, which could be prevented with a combination of interferon γ, tumor necrosis factor α/β, transforming growth factor β, interleukin-6 (IL-6) and IL-17 inhibitors. Single-cell RNA sequencing demonstrated upregulation of transcription factors associated with early stages of hematopoietic differentiation in the presence of spCAR (GATA2, RUNX1, CEBPA) and a decrease in the activity of key regulons involved in neutrophil and monocytic maturation (ID2 and MAFB). These results suggest that CAR-T activation induces HSPC maturation arrest through paracrine effects and provides potential treatments to mitigate the severity of this toxicity.

The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs).

How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Mesenchymal Stem Cells in Myelodysplastic Syndromes and Leukaemia.

Mesenchymal stem cells (MSCs) are one of the main residents in the bone marrow (BM) and have an essential role in the regulation of haematopoietic stem cell (HSC) differentiation and proliferation. Myelodysplastic syndromes (MDSs) are a group of myeloid disorders impacting haematopoietic stem and progenitor cells (HSCPs) that are characterised by BM failure, ineffective haematopoiesis, cytopenia, and a high risk of transformation through the expansion of MDS clones together with additional genetic defects. It has been indicated that MSCs play anti-tumorigenic roles such as in cell cycle arrest and pro-tumorigenic roles including the induction of metastasis in MDS and leukaemia. Growing evidence has shown that MSCs have impaired functions in MDS, such as decreased proliferation capacity, differentiation ability, haematopoiesis support, and immunomodulation function and increased inflammatory alterations within the BM through some intracellular pathways such as Notch and Wnt and extracellular modulators abnormally secreted by MSCs, including increased expression of inflammatory factors and decreased expression of haematopoietic factors, contributing to the development and progression of MDSs. Therefore, MSCs can be targeted for the treatment of MDSs and leukaemia. However, it remains unclear what drives MSCs to behave abnormally. In this review, dysregulations in MSCs and their contributions to myeloid haematological malignancies will be discussed.

Stochastic journeys of cell progenies through compartments and the role of self-renewal, symmetric and asymmetric division

Division and differentiation events by which cell populations with specific functions are generated often take place as part of a developmental programme, which can be represented by a sequence of compartments. A compartment is the set of cells with common characteristics; sharing, for instance, a spatial location or a phenotype. Differentiation events are transitions from one compartment to the next. Cells may also die or divide. We consider three different types of division events: (i) where both daughter cells inherit the mother’s phenotype (self-renewal), (ii) where only one of the daughters changes phenotype (asymmetric division), and (iii) where both daughters change phenotype (symmetric division). The self-renewal probability in each compartment determines whether the progeny of a single cell, moving through the sequence of compartments, is finite or grows without bound. We analyse the progeny stochastic dynamics with probability generating functions. In the case of self-renewal, by following one of the daughters after any division event, we may construct lifelines containing only one cell at any time. We analyse the number of divisions along such lines, and the compartment where lines terminate with a death event. Analysis and numerical simulations are applied to a five-compartment model of the gradual differentiation of hematopoietic stem cells and to a model of thymocyte development: from pre-double positive to single positive (SP) cells with a bifurcation to either SP4 or SP8 in the last compartment of the sequence.