Clonal hematopoiesis:a shared risk factor for cardiovascular diseases and tumors

Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation.Genes integral to critical cellular processes such as epigenetic regulation,DNA damage response,and inflammation frequently carry these mutations.Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions.Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis.Here,we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH,as well as look forward to future related studies,so as to provide valuable references for future research and clinical practice.

一类Hematopoiesis模型的唯一正周期解的存在性

本文考虑了一类Hematopoiesis模型,利用减算子的一个不动点定理,得到该方程存在唯一正周期解的充分条件,改进了已有文献的相应结果。特别地,本文还给出了收敛于该周期正解的迭代数列,即给出了该周期正解的近似表示。进而使本文的结果具有较大的实际应用价值。

脉冲Hematopoiesis模型的概周期解（英文）

获得了脉冲Hematopoiesis模型Q(t)=-c(t)Q(t)-α(t)Q(t)1+Q(t)+β(t)∫τ0F(u)Q(t-u)1+Q(t-u)dsΔQ(t k)=a k(t)Q(t k)+b k(t{)概周期解的存在性与指数稳定性.

Regulation of hematopoiesis and the hematopoietic stem cell niche by Wnt signaling pathways

Hematopoietic stem cells （HSCs） are a rare population of cells that are responsible for life-long generation of blood cells of all lineages. In order to maintain their numbers, HSCs must establish a balance between the opposing cell fates of self-renewal （in which the ability to function as HSCs is retained） and initiation of hematopoietic differentiation. Multiple signaling pathways have been implicated in the regulation of HSC cell fate. One such set of pathways are those activated by the Wnt family of ligands. Wnt signaling pathways play a crucial role during embryogenesis and deregulation of these pathways has been implicated in the formation of solid tumors. Wnt signaling also plays a role in the regulation of stem cells from multiple tissues, such as embryonic, epidermal, and intestinal stem cells. However, the function of Wnt signaling in HSC biology is still controversial. In this review, we will discuss the basic characteristics of the adult HSC and its regulatory microenvironment, the ＂niche＂, focusing on the regulation of the HSC and its niche by the Wnt signaling pathways.

Acquired aplastic anemia:Is bystander insult to autologous hematopoiesis driven by immune surveillance against malignant cells?

We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations(GCPs).This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments,with each recurrence occurring 7-8 wk from a GCP.After his third recurrence,he was prescribed successive treatment with rifampicin,berberine,and monthly administered GCP for 4 mo,and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy,and eventually died of septic shock.Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis.From the treatment process and laboratory investigations,it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state.Incorporation of rifampicin,berberine,and monthly GCP into cyclosporine can enhance the immunosuppressive effect.In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure,the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.

EFFECT OF RECOMBINANT MOUSE INTERLEUKIN-3 ON HEMATOPOIESIS IN NORMAL AND CYCLOPHOSPHAMIDE-TREATED MICE

Intraperitoneal injection of recombinant mouse IL-3 in normal mice for 6 days did not induce any significant changes in leukocyte and neutrophil counts. In comparison with saline controls, IL-3-treated mice experienced a 1.7-fold increase of bone marrow nucleated cells and 3.6-fold increase of CFU-GM colonies. Tritium thymidine incorporation of bone marrow cells significantly increased in IL-3-treated mice as compared with that in normal saline-treated mice. These results suggested that IL-3 expanded the number of granulocyte-macrophage progenitor cells but not the peripheral neutrophils. We examined the effect of IL-3 on hematopoietic reconstitution in a cyclophosphamide-treated mouse model. We found that the absolute neutrophil number of mice treated with IL-3 increased significantly on day 6 post injection when compared with the control mice (6.2± 4.1×109 / L versus 0.98± 1.4 × 109/ L, P【0.01) . The results demonstrated that IL-3 stimulated an early recovery of neutrophils after

Ikaros in hematopoiesis and leukemia

Ikaros is a gene whose activity is essential for normal hematopoiesis.Ikaros acts as a master regulator of lymphoid and myeloid development as well as a tumor suppressor.In cells,Ikaros regulates gene expression via chromatin remodeling.During the past 15 years tremendous advances have been made in understanding the role of Ikaros in hematopoiesis and leukemogenesis.In this Topic Highlights series of reviews,several groups of international experts in this field summarize the experimental data that is shaping the emerging picture of Ikaros function at the biochemical and cellular levels.The articles provide detailed analyses of recent scientific advancements and present models that will serve as a basis for future studies aimed at developing a better understanding of normal hematopoiesis and hematological malignancies and at accelerating the application of this knowledge in clinical practice.

Intestinal obstruction caused by extramedullary hematopoiesis and ascites in primary myelofibrosis

Primary myelofibrosis(PMF) is a clonal hematopoietic stem cell disorder. It is characterized by bone marrow fibrosis, extramedullary hematopoiesis with hepatosplenomegaly and leukoerythroblastosis in the peripheral blood. The main clinical manifestations of PMF are anemia, bleeding, hepatosplenomegaly, fatigue, and fever. Here we report a rare case of PMF with anemia, small bowel obstruction and ascites due to extramedullary hematopoiesis and portal hypertension. The diagnosis was difficult to establish before surgery and the differential diagnosis is discussed.

The evolving views of hematopoiesis:from embryo to adulthood and from in vivo to in vitro

The hematopoietic system composed of hematopoietic stem and progenitor cells(HSPCs)and their differentiated lineages serves as an ideal model to uncover generic principles of cell fate transitions.From gastrulation onwards,there successively emerge primitive hematopoiesis(that produces specialized he-matopoietic cells),pro-definitive hematopoiesis(that produces lineage-restricted progenitor cells),and definitive hematopoiesis(that produces multipotent HSPCs).These nascent lineages develop in several transient hematopoietic sites and finally colonize into lifelong hematopoietic sites.The development and maintenance of hematopoietic lineages are orchestrated by cell-intrinsic gene regulatory networks and cell-extrinsic microenvironmental cues.Owing to the progressive methodology(e.g.,high-throughput lineage tracing and single-cell functional and omics analyses),our understanding of the developmental origin of hematopoietic lineages and functional properties of certain hematopoietic organs has been updated;meanwhile,new paradigms to characterize rare cell types,cell heterogeneity and its causes,and comprehensive regulatory landscapes have been provided.Here,we review the evolving views of HSPC biology during developmental and postnatal hematopoiesis.Moreover,we discuss recent advances in the in vitro induction and expansion of HSPCs,with a focus on the implications for clinical applications.

Effect of Ligustrazine on Hematopoiesis in Bone Marrow Transplantation Mice

The effect of Ligustrazine on the hematopoiesis after bone marrow transplantation (BMT) in allogenic BMT mice was investigated. After the typical mice model of allogenic BMT had been established, the mice were randomly divided into three groups: BMT group, Ligustrazine group and normal group. The BMT group was given normal saline (0.2 ml, twice a day) through gastric tube, while the Ligustrazine group was given Ligustrazine through gastric tube (0.2 ml, twice a day). At the 1st, 7th and 14th day after BMT, we observed the peripheral blood cells and bone marrow nuclear cells (BMNC), as well as the expression level of Heparan Sulfate (HS) and stromal cell derived factor 1 (SDF 1) on bone marrow sections by using immunohistochemistry (SABC AP), the expression of CXCR4 on the BMNC. The results showed that on the 7th and 14th day, the peripheral blood white cells, platelets, BMNC and the expression levels of CXCR4, HS and SDF 1 were significantly higher in Ligustrazine group than in the BMT group ( P <0.05). It was concluded that Ligustrazine could promote hematopoiesis at the early stage of hematopoietic reconstitution after BMT.

Attractivity and Oscillation of Almost-periodic Solution for a Discrete Model of Hematopoiesis

By using a new fixed point theorem, sufficientconditions are obtained for the existence of a positivealmost-periodic solution for an discrete model of hematopoiesis with almost-periodic coefficients. Its attractivity and oscillation are investigated.

Intracranial Extramedullary Hematopoiesis in β-thalassemia Major

A case of β-thalassemia major with a huge mass of hernatopoictic tissuc firmly attached tothe dura mater was reported This is the first case reported in China.

Hematopoiesis reconstitution and anti-tumor effectiveness of Pai-Neng-Da capsule in acute leukemia patients with haploidentical hematopoietic stem cell transplantation

BACKGROUND With the rapid development of haploidentical hematopoietic stem cell transplantation(haplo-HSCT),primary poor graft function(PGF)has become a lifethreatening complication.Effective therapies for PGF are inconclusive.New Chinese patent medicine Pai-Neng-Da(PND)Capsule exerts dual effect in promoting hematopoiesis recovery and regulating immunity.Still,the application of PND capsule in hematopoietic stem cell transplantation,especially in the haplo-HSCT setting,has not yet been reported.AIM To evaluate the role of PND capsule in acute leukemia patients with haplo-HSCT.METHODS We retrospectively collected data of acute leukemia patients who underwent haplo-HSCT at the Affiliated People’s Hospital of Ningbo University between April 1,2015 and June 30,2020.Twenty-nine consecutive patients received oral PND capsule from the sixth day to the first month after haplo-HSCT were included in the PND group.In addition,31 patients who did not receive PND capsule during haplo-HSCT were included in the non-PND group.Subsequently,we compared the therapeutic efficacy according to the western medical evaluation indexes and Chinese medical symptom scores,and the survival between the PND group and the non-PND group,using the chi-square test,Fisher’s exact test,and the Kaplan-Meier method.RESULTS The duration of platelet engraftment was shorter in the PND group than in the non-PND group(P=0.039).The PND group received a lower frequency of red blood cells and platelet transfusions than the non-PND group(P=0.033 and P=0.035,respectively).In addition,PND capsule marginally reduced the rate of PGF(P=0.027)and relapse(P=0.043).After 33(range,4-106)months of follow-up,the 3-year relapse-free survival(P=0.046)and progression-free survival(P=0.049)were improved in the PND group than in the non-PND group.Also,the therapeutic efficacy of the PND group according to Chinese medical symptom scores was significantly better than that of the non-PND group(P=0.022).Moreover,the adverse events caused by PND capsule were mild.Nevertheless,there were no significant differences in the duration of neutrophil engraftment,the risk of infection within 100 days after haplo-HSCT,the acute graft-versus-host disease,or the 3-year overall survival between the two groups.CONCLUSION PND capsule could promote hematopoiesis reconstitution,improve the therapeutic efficacy of Chinese medical symptom scores,present anti-tumor effectiveness,and prolong the survival of acute leukemia patients with haplo-HSCT.

Magnetic resonance imaging features of intrahepatic extramedullary hematopoiesis: Three case reports

BACKGROUND Extramedullary hematopoiesis rarely occurs within the liver alone,and is easily misdiagnosed.The radiological literature on this disease is exclusively case reports.There is a paucity of literature on the role of magnetic resonance imaging(MRI).The most common imaging modalities used are computed tomography and ultrasound.This report aims to provide more data on the appearance of extramedullary hematopoiesis using MRI to help radiologists establish the diagnosis.CASE SUMMARY Three patients(one male and two females)were incidentally found to have a hepatic mass or nodule,without hepatomegaly or splenomegaly.Laboratory tests including liver function,serum hepatic tumor markers,and hepatitis serologic markers were normal.On MRI scans,all lesions showed lower signal intensity on in-phase images than on out-phase images.One case showed changes in signal intensity on T2 weighted images(WI)and diffusion WI,which shifted from hyperintensity to hypointensity with size enlargement between two rounds of imaging examination.These lesions exhibited different enhancement patterns on dynamic contrast enhancement series.CONCLUSION The MRI signal change and in-/out-phase image might provide useful information and help radiologists establish the diagnosis of intrahepatic extramedullary hematopoiesis.

Weighted Pseudo Almost Periodic Solutions for a Class of Hematopoiesis Model with Time-Varying Delay

In this paper, firstly, a notion of a class of generalized weighted pseudo al- most periodic function is introduced, then we investigate some basic and essential properties of the space that consists of these functions. Finally, we study the exis- tence of weighted pseudo almost periodic solutions to hematopoiesis model with time- varying delay.

Traveling Wavefronts of a Diffusive Hematopoiesis Model with Time Delay

In this paper, a reaction-diffusion equation with discrete time delay that describes the dynamics of the blood cell production is analyzed. The existence of the traveling wave front solutions is demonstrated using the technique of upper and lower solutions and the associated monotone iteration.

Extramedullary Hematopoiesis Mimicking a Neoplasm in a Goeldi＇s Monkey （Callimico goeldii）

Extramedullary hematopoiesis consists in the appearance and proliferation of hematopoietic cells outside the bone marrow. In this article, the authors describe a case of hepatosplenic hematopoiesis in a 9-year-old, male Goeldi＇s monkey concurrent with a Calodium hepaticum infestation, belonging to the Lisbon＇s Zoo primate collection （Portugal）. Lesions were identified upon necropsy after euthanasia due to the presence of an apparently non-excisable, metastatic aortic mass. Histopathological analysis of samples taken was carried out and immunohistochemical staining was used to characterize the cellular population involved, confirming the diagnosis of extramedullary hematopoiesis. To the best of the authors＇ knowledge, this is the first report of hepatosplenic extramedullary hematopoiesis in a Goeldi＇s monkey.

Bone-marrow derived cells participate in extramedullary hematopoiesis in a model of acetaminophen-induced acute liver failure in rats

Adult derived mononuclear bone marrow cells are a good alternative as cell therapy. These cells are capable of significantly improve survival rate of Wistar rats with acetaminophen (APAP) induced acute liver failure in ten days. However, long term of cell therapy is not deeply studied in the literature. Here, we report an extramedullary hematopoiesis process derived from transplanted mononuclear bone marrow cells in the liver of rats 10 days after APAP injection. This result indicates that liver maintains an adequate microenvironment for the occurrence of extramedullary hematopoiesis process. The consequence of this finding deserves more studies.

Ossified thoracic spinal meningioma with hematopoiesis: A case report and review of the literature

Meningiomas account for 25% of spinal tumors, and they are often located in the thoracic spine. The ossified subtype is even rarer, and those with hematopoiesis are rarely described. The mechanism of bone formation has not yet been clarified. A case of ossified spinal meningioma with hematopoiesis occurring in a 78-year-old woman is described. Magnetic resonance imaging revealed a lesion with a dural tail sign at the T9 level located dorsal to the spinal cord. Computerized tomography revealed a high density lesion, as high as the bone signal. Total resection was performed, and the symptoms improved. Pathological findings revealed many psammoma bodies (PBs), bone formation, and bone marrow with hematopoiesis. Both PBs and bone seemed to be based on the same background of calcified structures. This report is the second dealing with ossified spinal meningioma with hematopoiesis. The hardness of the tumor can make the operation more difficult, so that the operation should be performed carefully to avoid injuring the spinal cord.

Genome and clonal hematopoiesis stability contrasts with immune,cfDNA,mitochondrial,and telomere length changes during short duration spaceflight

Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth.CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career astronauts.This study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.