Efforts to promote recovery of function after human spinal cord injury(SCI) will likely require interventions to rgeting the corticospinal tract(CST) motor system:the most important pathway for voluntary motor control...Efforts to promote recovery of function after human spinal cord injury(SCI) will likely require interventions to rgeting the corticospinal tract(CST) motor system:the most important pathway for voluntary motor control in humans.This system has historically been the most refractory to regenerative efforts after SCI.The "nonregeneration" of the CST changed when robust regeneration of the CST into spared tissue was demonstrated by the inactivation of phosphatase and tensin homolog and delivery of inosine.展开更多
Temporal lobe epilepsy(TLE) is a common type of focal epilepsy characterized by seizure foci within the temporal lobes.While surgical resection of the foci is an established and effective approach for controlling seiz...Temporal lobe epilepsy(TLE) is a common type of focal epilepsy characterized by seizure foci within the temporal lobes.While surgical resection of the foci is an established and effective approach for controlling seizures,both temporal lobes cannot be removed,due to their prominent roles in learning and memory.Additionally,seizures induce changes to the temporal lobes that contribute to hyperexcitability,including mossy fiber sprouting,astrogliosis.展开更多
Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a p...Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a promising treatment for Parkinson’s disease.However,transplanted cells can be injured by mechanical damage during handling and by changes in the transplantation niche.Here,we developed a one-step biomanufacturing platform that uses small-aperture gelatin microcarriers to produce beads carrying midbrain dopaminergic progenitor cells.These beads allow midbrain dopaminergic progenitor cell differentiation and cryopreservation without digestion,effectively maintaining axonal integrity in vitro.Importantly,midbrain dopaminergic progenitor cell bead grafts showed increased survival and only mild immunoreactivity in vivo compared with suspended midbrain dopaminergic progenitor cell grafts.Overall,our findings show that these midbrain dopaminergic progenitor cell beads enhance the effectiveness of neuronal cell transplantation.展开更多
Recent results emphasize the supportive effects of adipose-derived multipotent stem/progenitor cells(ADSPCs)in peripheral nerve recovery.Cultivation under hypoxia is considered to enhance the release of the regenerati...Recent results emphasize the supportive effects of adipose-derived multipotent stem/progenitor cells(ADSPCs)in peripheral nerve recovery.Cultivation under hypoxia is considered to enhance the release of the regenerative potential of ADSPCs.This study aimed to examine whether peripheral nerve regeneration in a rat model of autologous sciatic nerve graft benefits from an additional custom-made fibrin conduit seeded with hypoxic pre-conditioned(2%oxygen for 72 hours)autologous ADSPCs(n=9).This treatment mode was compared with three others:fibrin conduit seeded with ADSPCs cultivated under normoxic conditions(n=9);non-cell-carrying conduit(n=9);and nerve autograft only(n=9).A 16-week follow-up included functional testing(sciatic functional index and static sciatic index)as well as postmortem muscle mass analyses and morphometric nerve evaluations(histology,g-ratio,axon density,and diameter).At 8 weeks,the hypoxic pre-conditioned group achieved significantly higher sciatic functional index/static sciatic index scores than the other three groups,indicating faster functional regeneration.Furthermore,histologic evaluation showed significantly increased axon outgrowth/branching,axon density,remyelination,and a reduced relative connective tissue area.Hypoxic pre-conditioned ADSPCs seeded in fibrin conduits are a promising adjunct to current nerve autografts.Further studies are needed to understand the underlying cellular mechanism and to investigate a potential application in clinical practice.展开更多
Neural progenitor cells(NPCs) capable of self-renewal and differentiation into neural cell lineages offer broad prospects for cell therapy for neurodegenerative diseases. However, cell therapy based on NPC transplanta...Neural progenitor cells(NPCs) capable of self-renewal and differentiation into neural cell lineages offer broad prospects for cell therapy for neurodegenerative diseases. However, cell therapy based on NPC transplantation is limited by the inability to acquire sufficient quantities of NPCs. Previous studies have found that a chemical cocktail of valproic acid, CHIR99021, and Repsox(VCR) promotes mouse fibroblasts to differentiate into NPCs under hypoxic conditions. Therefore, we used VCR(0.5 mM valproic acid, 3 μM CHIR99021, and 1 μM Repsox) to induce the reprogramming of rat embryonic fibroblasts into NPCs under a hypoxic condition(5%). These NPCs exhibited typical neurosphere-like structures that can express NPC markers, such as Nestin, SRY-box transcription factor 2, and paired box 6(Pax6), and could also differentiate into multiple types of functional neurons and astrocytes in vitro. They had similar gene expression profiles to those of rat brain-derived neural stem cells. Subsequently, the chemically-induced NPCs(ciNPCs) were stereotactically transplanted into the substantia nigra of 6-hydroxydopamine-lesioned parkinsonian rats. We found that the ciNPCs exhibited long-term survival, migrated long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Moreover, the parkinsonian behavioral defects of the parkinsonian model rats grafted with ciNPCs showed remarkable functional recovery. These findings suggest that rat fibroblasts can be directly transformed into NPCs using a chemical cocktail of VCR without introducing exogenous factors, which may be an attractive donor material for transplantation therapy for Parkinson’s disease.展开更多
Genome duplication events,comprising whole-genome duplication and single-gene duplication,produce a complex genomic context leading to multiple levels of genetic changes.However,the characteristics of m^(6)A modificat...Genome duplication events,comprising whole-genome duplication and single-gene duplication,produce a complex genomic context leading to multiple levels of genetic changes.However,the characteristics of m^(6)A modification,the most widespread internal eukaryotic mRNA modification,in polyploid species are still poorly understood.This study revealed the characteristics of m^(6)A methylomes within the early formation and following the evolution of allopolyploid Brassica napus.We found a complex relationship between m^(6)A modification abundance and gene expression level depending on the degree of enrichment or presence/absence of m^(6)A modification.Overall,the m^(6)A genes had lower gene expression levels than the non-m^(6)A genes.Allopolyploidization may change the expression divergence of duplicated gene pairs with identical m^(6)A patterns and diverged m^(6)A patterns.Compared with duplicated genes,singletons with a higher evolutionary rate exhibited higher m^(6)A modification.Five kinds of duplicated genes exhibited distinct distributions of m^(6)A modifications in transcripts and gene expression level.In particular,tandem duplication-derived genes showed unique m^(6)A modification enrichment around the transcript start site.Active histone modifications(H3K27ac and H3K4me3)but not DNA methylation were enriched around genes of m^(6)A peaks.These findings provide a new understanding of the features of m 6A modification and gene expression regulation in allopolyploid plants with sophisticated genomic architecture.展开更多
Lysosomal storage diseases:Lysosomal storage diseases(LSDs) are a family of about 70 disorders,with an overall incidence of 1:7000 live births.They are caused by dysfunctional lysosomal hydrolases,eventually leading t...Lysosomal storage diseases:Lysosomal storage diseases(LSDs) are a family of about 70 disorders,with an overall incidence of 1:7000 live births.They are caused by dysfunctional lysosomal hydrolases,eventually leading to the accumulation of undegraded substrate into the lysosome.This results in a wide array of symptoms,which may include:the presence of dysmorphic features,cardio-respiratory disease,bone and joint disease,organomegaly,developmental delay and neurocognitive decline.The majority of these diseases have a neurological component and in the absence of treatment.展开更多
Alzheimer’s disease(AD)is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly.Considering AD to be an epidemic,an increase from the current 50 million to more than 150 milli...Alzheimer’s disease(AD)is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly.Considering AD to be an epidemic,an increase from the current 50 million to more than 150 million patients is expected by the year 2050.展开更多
The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development.However,its function in retina regeneration remains elusive.Here we report that Sox11 b,a zebrafish Sox11 ...The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development.However,its function in retina regeneration remains elusive.Here we report that Sox11 b,a zebrafish Sox11 homolog,regulates the migration and fate determination of Müller glia-derived progenitors(MGPCs)in an adult zebrafish model of mechanical retinal injury.Following a stab injury,the expression of Sox11 b was induced in proliferating MGPCs in the retina.Sox11 b knockdown did not affect MGPC formation at 4 days post-injury,although the nuclear morphology and subsequent radial migration of MGPCs were alte red.At 7 days post-injury,Sox11 b knockdown res ulted in an increased proportion of MGPCs in the inner retina and a decreased propo rtion of MGPCs in the outer nuclear layer,compared with controls.Furthermore,Sox11 b knockdown led to reduced photoreceptor regeneration,while it increased the numbe rs of newborn amacrines and retinal ganglion cells.Finally,quantitative polymerase chain reaction analysis revealed that Sox11 b regulated the expression of Notch signaling components in the retina,and Notch inhibition partially recapitulated the Sox11 b knockdown phenotype,indicating that Notch signaling functions downstream of Sox11 b.Our findings imply that Sox11 b plays key roles in MGPC migration and fate determination during retina regeneration in zebrafish,which may have critical im plications for future explorations of retinal repair in mammals.展开更多
A distinct population of skeletal stem/progenitor cells(SSPCs)has been identified that is indispensable for the maintenance and remodeling of the adult skeleton.However,the cell types that are responsible for age-rela...A distinct population of skeletal stem/progenitor cells(SSPCs)has been identified that is indispensable for the maintenance and remodeling of the adult skeleton.However,the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined.Here,we established models of premature aging by conditional depletion of Zmpste24(Z24)in mice and found that Prx1-dependent Z24 deletion,but not Osx-dependent Z24 deletion,caused significant bone loss.However,Acan-associated Z24 depletion caused only trabecular bone loss.Single-cell RNA sequencing(sc RNA-seq)revealed that two populations of SSPCs,one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells,were significantly decreased in Prx1-Cre;Z24^(f/f)mice.Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation.Physical exercise reversed the effects of Z24depletion on cellular apoptosis,extracellular matrix expression and bone mass.This study identified two populations of SSPCs that are responsible for premature aging-related bone loss.The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.展开更多
Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate,where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone.The chondroprogenitors in the re...Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate,where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone.The chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate.Malnutrition is a leading cause of growth retardation in children;however,after recovery from nutrient deprivation,bone growth is accelerated beyond the normal rate,a phenomenon termed catch-up growth.Although nutritional status is a known regulator of long bone growth,it is largely unknown whether and how chondroprogenitor cells respond to deviations in nutrient availability.Here,using fate-mapping analysis in Axin2CreERT2 mice,we showed that dietary restriction increased the number of Axin2+chondroprogenitors in the resting zone and simultaneously inhibited their differentiation.Once nutrient deficiency was resolved,the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns,contributing to accelerated growth.Furthermore,we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone and that exogenous IGF-1 restored the phosphorylated Akt level and stimulated differentiation of the pooled chondroprogenitors,decreasing their numbers.Our study of Axin2CreERT2 revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of chondroprogenitor cells.展开更多
Heterotopic ossification(HO)is a pathological process resulting in aberrant bone formation and often involves synovial lined tissues.During this process,mesenchymal progenitor cells undergo endochondral ossification.N...Heterotopic ossification(HO)is a pathological process resulting in aberrant bone formation and often involves synovial lined tissues.During this process,mesenchymal progenitor cells undergo endochondral ossification.Nonetheless,the specific cell phenotypes and mechanisms driving this process are not well understood,in part due to the high degree of heterogeneity of the progenitor cells involved.Here,using a combination of lineage tracing and single-cell RNA sequencing(sc RNA-seq),we investigated the extent to which synovial/tendon sheath progenitor cells contribute to heterotopic bone formation.For this purpose,Tppp3(tubulin polymerization-promoting protein family member 3)-inducible reporter mice were used in combination with either Scx(Scleraxis)or Pdgfra(platelet derived growth factor receptor alpha)reporter mice.Both tendon injury-and arthroplasty-induced mouse experimental HO models were utilized.Sc RNA-seq of tendon-associated traumatic HO suggested that Tppp3 is an early progenitor cell marker for either tendon or osteochondral cells.Upon HO induction,Tppp3 reporter^(+)cells expanded in number and partially contributed to cartilage and bone formation in either tendon-or joint-associated HO.In double reporter animals,both Pdgfra^(+)Tppp3^(+)and Pdgfra^(+)Tppp3^(-) progenitor cells gave rise to HO-associated cartilage.Finally,analysis of human samples showed a substantial population of TPPP3^(-) expressing cells overlapping with osteogenic markers in areas of heterotopic bone.Overall,these data demonstrate that synovial/tendon sheath progenitor cells undergo aberrant osteochondral differentiation and contribute to HO after trauma.展开更多
Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we ...Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.展开更多
AIM:To explore whether the subretinal transplantation of retinal progenitor cells from human embryonic stem cell-derived retinal organoid(h ERO-RPCs)could promote Müller glia dedifferentiation and transdifferenti...AIM:To explore whether the subretinal transplantation of retinal progenitor cells from human embryonic stem cell-derived retinal organoid(h ERO-RPCs)could promote Müller glia dedifferentiation and transdifferentiation,thus improving visual function and delaying retinal degenerative progression.METHODS:h ERO-RPCs were subretinally transplanted into Royal College of Surgeons(RCS)rats.Electroretinography(ERG)recording was performed at 4 and 8wk postoperation to assess retinal function.Using immunofluorescence,the changes in outer nuclear layer(ONL)thickness and retinal Müller glia were explored at 2,4,and 8wk postoperation.To verify the effect of h ERO-RPCs on Müller glia in vitro,we cocultured h ERO-RPCs with Müller glia with a Transwell system.After coculture,Ki67 staining and quantitative polymerase chain reaction(q PCR)were performed to measure the proliferation and m RNA levels of Müller glia respectively.Cell migration experiment was used to detect the effect of h ERO-RPCs on Müller glial migration.Comparisons between two groups were performed by the unpaired Student’s t-test,and comparisons among multiple groups were made with one-way ANOVA followed by Tukey’s multiple comparison test.RESULTS:The visual function and ONL thickness of RCS rats were significantly improved by transplantation of h ERO-RPCs at 4 and 8wk postoperation.In addition to inhibiting gliosis at 4 and 8wk postoperation,h ERO-RPCs significantly increased the expression of dedifferentiation-associated transcriptional factor in Müller glia and promoted the migration at 2,4 and 8wk postoperation,but not the transdifferentiation of these cells in RCS rats.In vitro,using the Transwell system,we found that h ERO-RPCs promoted the proliferation and migration of primary rat Müller glia and induced their dedifferentiation at the m RNA level.CONCLUSION:These results show that h ERO-RPCs might promote early dedifferentiation of Müller glia,which may provide novel insights into the mechanisms of stem cell therapy and Müller glial reprogramming,contributing to the development of novel therapies for retinal degeneration disorders.展开更多
AIM:To observe the effect of low oxygen concentration on the neural retina in human induced pluripotent stem cell(hiPSC)-derived retinal organoids(ROs).METHODS:The hiPSC and a three-dimensional culture method were use...AIM:To observe the effect of low oxygen concentration on the neural retina in human induced pluripotent stem cell(hiPSC)-derived retinal organoids(ROs).METHODS:The hiPSC and a three-dimensional culture method were used for the experiments.Generated embryoid bodies(EBs)were randomly and equally divided into hypoxic and normoxic groups.Photographs of the EBs were taken on days 38,45,and 52,and the corresponding volume of EBs was calculated.Simultaneously,samples were collected at these three timepoints,followed by fixation,sectioning,and immunofluorescence.RESULTS:The proportion of Ki67-positive proliferating cells increased steadily on day 38;this proliferationpromoting effect tended to increase tissue density rather than tissue volume.On days 45 and 52,the two groups had relatively similar ratios of Ki67-positive cells.Further immunofluorescence analysis showed that the ratio of SOX2-positive cells significantly increased within the neural retina on day 52(P<0.05).In contrast,the percentage of PAX6-and CHX10-positive cells significantly decreased following hypoxia treatment at all three timepoints(P<0.01),except for CHX10 at day 45(P>0.05).Moreover,the proportion of PAX6-/TUJ1+cells within the neural retinas increased considerably(P<0.01,<0.05,<0.05 respectively).CONCLUSION:Low oxygen promotes stemness and proliferation of neural retinas,suggesting that hypoxic conditions can enlarge the retinal progenitor cell pool in hiPSC-derived ROs.展开更多
Different fates of neural stem/progenitor cells(NSPCs)and their progeny are determined by the gene regulatory network,where a chromatin-remodeling complex affects synergy with other regulators.Here,we review recent re...Different fates of neural stem/progenitor cells(NSPCs)and their progeny are determined by the gene regulatory network,where a chromatin-remodeling complex affects synergy with other regulators.Here,we review recent research progress indicating that the BRG1/BRM-associated factor(BAF)complex plays an important role in NSPCs during neural development and neural developmental disorders.Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation,which can also lead to various diseases in humans.We discussed BAF complex subunits and their main characteristics in NSPCs.With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs,we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs.Considering recent progress in these research areas,we suggest that three approaches should be used in investigations in the near future.Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders.More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.展开更多
Vascular injury is a frequent pathology in coronary artery disease.To repair the vasculature,scientists have found that endothelial progenitor cells(EPCs)have excellent properties associated with angiogenesis.Over tim...Vascular injury is a frequent pathology in coronary artery disease.To repair the vasculature,scientists have found that endothelial progenitor cells(EPCs)have excellent properties associated with angiogenesis.Over time,research on EPCs has made encouraging progress regardless of pathology or clinical technology.This review focuses on the origins and cell markers of EPCs,and the connection between EPCs and coronary artery disease.In addition,we summarized various studies of EPC-capturing stents and EPC infusion therapy,and aim to learn from past technology to predict the future.展开更多
Most hematopoietic stem progenitor cells (HSPCs) reside in bone marrow (BM), but a small amount of HSPCs have been found to circulate between BM and tissues through blood and lymph. Several lines of evidence suggest t...Most hematopoietic stem progenitor cells (HSPCs) reside in bone marrow (BM), but a small amount of HSPCs have been found to circulate between BM and tissues through blood and lymph. Several lines of evidence suggest that sphingosine-1-phosphate (S1P) gradient triggers HSPC egression to blood circulation after mobilization from BM stem cell niches. Stem cells also visit certain tissues. After a temporary 36 h short stay in local tissues, HSPCs go to lymph in response to S1P gradient between lymph and tissue and eventually enter the blood circulation. S1P also has a role in the guidance of the primitive HSPCs homing to BM in vivo, as S1P analogue FTY720 treatment can improve HSPC BM homing and engraftment. In stress conditions, various stem cells or progenitor cells can be attracted to local injured tissues and participate in local tissue cell differentiation and tissue rebuilding through modulation the expression level of S1P1, S1P2 or S1P3 receptors. Hence, S1P is important for stem cells circulation in blood system to accomplish its role in body surveillance and injury recovery.展开更多
Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells(EPCs) are derived from hematopoietic stem cells and are capable of fo...Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells(EPCs) are derived from hematopoietic stem cells and are capable of forming new blood vessels through a process of vas-culogenesis. There are studies which report correlations between circulating EPCs and cardiovascular risk fac-tors. There are also studies on how pharmacotherapies may influence levels of circulating EPCs. In this review, we discuss the potential role of endothelial progenitor cells as both diagnostic and prognostic biomarkers. In addition, we look at the interaction between cardio-vascular pharmacotherapies and endothelial progenitor cells. We also discuss how EPCs can be used directly and indirectly as a therapeutic agent. Finally, we evalu-ate the challenges facing EPC research and how these may be overcome.展开更多
Circulating bone-marrow-derived cells,named endothelial progenitor cells(EPCs),are capable of maintaining,generating,and replacing terminally differentiated cells within their own specific tissue as a consequence of p...Circulating bone-marrow-derived cells,named endothelial progenitor cells(EPCs),are capable of maintaining,generating,and replacing terminally differentiated cells within their own specific tissue as a consequence of physiological cell turnover or tissue damage due to injury.Endothelium maintenance and restoration of normal endothelial cell function is guaranteed by a complex physiological procedure in which EPCs play a significant role.Decreased number of peripheral blood EPCs has been associated with endothelial dysfunction and high cardiovascular risk.In this review,we initially report current knowledge with regard to the role of EPCs in healthy subjects and the clinical value of EPCs in different disease populations such as arterial hypertension,obstructive sleep-apnea syndrome,obesity,diabetes mellitus,peripheral arterial disease,coronary artery disease,pulmonary hypertension,and heart failure.Recent studies have introduced the novel concept that physical activity,either performed as a single exercise session or performed as part of an exercise training program,results in a significant increase of circulating EPCs.In the second part of this review we provide preliminary evidence from recent studies investigating the effects of acute and long-term exercise in healthy subjects and athletes as well as in disease populations.展开更多
基金supported by the Veterans Administration (I01RX002264-01A2)(to PL)Wings For Life (WFL-US-10/21)(to CMF)。
文摘Efforts to promote recovery of function after human spinal cord injury(SCI) will likely require interventions to rgeting the corticospinal tract(CST) motor system:the most important pathway for voluntary motor control in humans.This system has historically been the most refractory to regenerative efforts after SCI.The "nonregeneration" of the CST changed when robust regeneration of the CST into spared tissue was demonstrated by the inactivation of phosphatase and tensin homolog and delivery of inosine.
文摘Temporal lobe epilepsy(TLE) is a common type of focal epilepsy characterized by seizure foci within the temporal lobes.While surgical resection of the foci is an established and effective approach for controlling seizures,both temporal lobes cannot be removed,due to their prominent roles in learning and memory.Additionally,seizures induce changes to the temporal lobes that contribute to hyperexcitability,including mossy fiber sprouting,astrogliosis.
基金supported by the National Key Research and Development Program of China,Nos.2017YFE0122900(to BH),2019YFA0110800(to WL),2019YFA0903802(to YW),2021YFA1101604(to LW),2018YFA0108502(to LF),and 2020YFA0804003(to JW)the National Natural Science Foundation of China,Nos.31621004(to WL,BH)and 31970821(to YW)+1 种基金CAS Project for Young Scientists in Basic Research,No.YSBR-041(to YW)Joint Funds of the National Natural Science Foundation of China,No.U21A20396(to BH)。
文摘Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a promising treatment for Parkinson’s disease.However,transplanted cells can be injured by mechanical damage during handling and by changes in the transplantation niche.Here,we developed a one-step biomanufacturing platform that uses small-aperture gelatin microcarriers to produce beads carrying midbrain dopaminergic progenitor cells.These beads allow midbrain dopaminergic progenitor cell differentiation and cryopreservation without digestion,effectively maintaining axonal integrity in vitro.Importantly,midbrain dopaminergic progenitor cell bead grafts showed increased survival and only mild immunoreactivity in vivo compared with suspended midbrain dopaminergic progenitor cell grafts.Overall,our findings show that these midbrain dopaminergic progenitor cell beads enhance the effectiveness of neuronal cell transplantation.
基金support by the Faculty of Medicine,Ludwig-Maximilians-University(FöFoLe,Project 843 and 955,to TH and MMS).
文摘Recent results emphasize the supportive effects of adipose-derived multipotent stem/progenitor cells(ADSPCs)in peripheral nerve recovery.Cultivation under hypoxia is considered to enhance the release of the regenerative potential of ADSPCs.This study aimed to examine whether peripheral nerve regeneration in a rat model of autologous sciatic nerve graft benefits from an additional custom-made fibrin conduit seeded with hypoxic pre-conditioned(2%oxygen for 72 hours)autologous ADSPCs(n=9).This treatment mode was compared with three others:fibrin conduit seeded with ADSPCs cultivated under normoxic conditions(n=9);non-cell-carrying conduit(n=9);and nerve autograft only(n=9).A 16-week follow-up included functional testing(sciatic functional index and static sciatic index)as well as postmortem muscle mass analyses and morphometric nerve evaluations(histology,g-ratio,axon density,and diameter).At 8 weeks,the hypoxic pre-conditioned group achieved significantly higher sciatic functional index/static sciatic index scores than the other three groups,indicating faster functional regeneration.Furthermore,histologic evaluation showed significantly increased axon outgrowth/branching,axon density,remyelination,and a reduced relative connective tissue area.Hypoxic pre-conditioned ADSPCs seeded in fibrin conduits are a promising adjunct to current nerve autografts.Further studies are needed to understand the underlying cellular mechanism and to investigate a potential application in clinical practice.
基金supported by the National Natural Science Foundation of China,No. 81771381 (to CQL)Anhui Provincial Key Research and Development Project,Nos. 2022e07020030 (to CQL), 2022e07020032 (to YG)+2 种基金Science Research Project of Bengbu Medical College,No. 2021byfy002 (to CQL)the Natural Science Foundation of the Higher Education Institutions of Anhui Province,No. KJ2021ZD0085 (to CJW)the Undergraduate Innovative Training Program of China,Nos. 202110367043 (to CQL), 202110367044 (to YG)。
文摘Neural progenitor cells(NPCs) capable of self-renewal and differentiation into neural cell lineages offer broad prospects for cell therapy for neurodegenerative diseases. However, cell therapy based on NPC transplantation is limited by the inability to acquire sufficient quantities of NPCs. Previous studies have found that a chemical cocktail of valproic acid, CHIR99021, and Repsox(VCR) promotes mouse fibroblasts to differentiate into NPCs under hypoxic conditions. Therefore, we used VCR(0.5 mM valproic acid, 3 μM CHIR99021, and 1 μM Repsox) to induce the reprogramming of rat embryonic fibroblasts into NPCs under a hypoxic condition(5%). These NPCs exhibited typical neurosphere-like structures that can express NPC markers, such as Nestin, SRY-box transcription factor 2, and paired box 6(Pax6), and could also differentiate into multiple types of functional neurons and astrocytes in vitro. They had similar gene expression profiles to those of rat brain-derived neural stem cells. Subsequently, the chemically-induced NPCs(ciNPCs) were stereotactically transplanted into the substantia nigra of 6-hydroxydopamine-lesioned parkinsonian rats. We found that the ciNPCs exhibited long-term survival, migrated long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Moreover, the parkinsonian behavioral defects of the parkinsonian model rats grafted with ciNPCs showed remarkable functional recovery. These findings suggest that rat fibroblasts can be directly transformed into NPCs using a chemical cocktail of VCR without introducing exogenous factors, which may be an attractive donor material for transplantation therapy for Parkinson’s disease.
基金This work was supported by the National Natural Science Foundation of China(31970241).
文摘Genome duplication events,comprising whole-genome duplication and single-gene duplication,produce a complex genomic context leading to multiple levels of genetic changes.However,the characteristics of m^(6)A modification,the most widespread internal eukaryotic mRNA modification,in polyploid species are still poorly understood.This study revealed the characteristics of m^(6)A methylomes within the early formation and following the evolution of allopolyploid Brassica napus.We found a complex relationship between m^(6)A modification abundance and gene expression level depending on the degree of enrichment or presence/absence of m^(6)A modification.Overall,the m^(6)A genes had lower gene expression levels than the non-m^(6)A genes.Allopolyploidization may change the expression divergence of duplicated gene pairs with identical m^(6)A patterns and diverged m^(6)A patterns.Compared with duplicated genes,singletons with a higher evolutionary rate exhibited higher m^(6)A modification.Five kinds of duplicated genes exhibited distinct distributions of m^(6)A modifications in transcripts and gene expression level.In particular,tandem duplication-derived genes showed unique m^(6)A modification enrichment around the transcript start site.Active histone modifications(H3K27ac and H3K4me3)but not DNA methylation were enriched around genes of m^(6)A peaks.These findings provide a new understanding of the features of m 6A modification and gene expression regulation in allopolyploid plants with sophisticated genomic architecture.
文摘Lysosomal storage diseases:Lysosomal storage diseases(LSDs) are a family of about 70 disorders,with an overall incidence of 1:7000 live births.They are caused by dysfunctional lysosomal hydrolases,eventually leading to the accumulation of undegraded substrate into the lysosome.This results in a wide array of symptoms,which may include:the presence of dysmorphic features,cardio-respiratory disease,bone and joint disease,organomegaly,developmental delay and neurocognitive decline.The majority of these diseases have a neurological component and in the absence of treatment.
基金partially supported by grants from the Xunta de Galicia(IN607A2018/3 to TS,IN607D 2020/09 to TS,IN606A-2021/015 to ACIN606B-2021/010 to DRS)+3 种基金Science Ministry of Spain(RTI2018-102165-B-I00 to TS,RTC2019007373-1 to TS)supported by grants from the INTERREG Atlantic Area(EAPA_791/2018_NEUROATLANTIC project to TS)INTER-REG V A España Portugal(POCTEP)(0624_2IQBIONEURO_6_E to TS)the European Regional Development Fund(ERDF)。
文摘Alzheimer’s disease(AD)is the main neurodegenerative disease leading to dementia and cognitive impairment in the elderly.Considering AD to be an epidemic,an increase from the current 50 million to more than 150 million patients is expected by the year 2050.
基金supported by the National Key Research and Development Project of China,Nos.2017YFA0104100(to JL),2017YFA0701304(to HX)National Natural Science Foundation of China Nos.81970820(to HX),31930068(to JL)。
文摘The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development.However,its function in retina regeneration remains elusive.Here we report that Sox11 b,a zebrafish Sox11 homolog,regulates the migration and fate determination of Müller glia-derived progenitors(MGPCs)in an adult zebrafish model of mechanical retinal injury.Following a stab injury,the expression of Sox11 b was induced in proliferating MGPCs in the retina.Sox11 b knockdown did not affect MGPC formation at 4 days post-injury,although the nuclear morphology and subsequent radial migration of MGPCs were alte red.At 7 days post-injury,Sox11 b knockdown res ulted in an increased proportion of MGPCs in the inner retina and a decreased propo rtion of MGPCs in the outer nuclear layer,compared with controls.Furthermore,Sox11 b knockdown led to reduced photoreceptor regeneration,while it increased the numbe rs of newborn amacrines and retinal ganglion cells.Finally,quantitative polymerase chain reaction analysis revealed that Sox11 b regulated the expression of Notch signaling components in the retina,and Notch inhibition partially recapitulated the Sox11 b knockdown phenotype,indicating that Notch signaling functions downstream of Sox11 b.Our findings imply that Sox11 b plays key roles in MGPC migration and fate determination during retina regeneration in zebrafish,which may have critical im plications for future explorations of retinal repair in mammals.
基金supported by the National Natural Science Foundation of China (NSFC) (82230082,81991512 to W.Z.,82202742 to J.S.,82070108 to R.Y.)the National Key Research and Development Program of China (2022YFA0806600 to W.Z.,2022YFA1103200 to R.Y.)CAS Project for Young Scientists in Basic Research (YSBR077 to W.Z.)。
文摘A distinct population of skeletal stem/progenitor cells(SSPCs)has been identified that is indispensable for the maintenance and remodeling of the adult skeleton.However,the cell types that are responsible for age-related bone loss and the characteristic changes in these cells during aging remain to be determined.Here,we established models of premature aging by conditional depletion of Zmpste24(Z24)in mice and found that Prx1-dependent Z24 deletion,but not Osx-dependent Z24 deletion,caused significant bone loss.However,Acan-associated Z24 depletion caused only trabecular bone loss.Single-cell RNA sequencing(sc RNA-seq)revealed that two populations of SSPCs,one that differentiates into trabecular bone cells and another that differentiates into cortical bone cells,were significantly decreased in Prx1-Cre;Z24^(f/f)mice.Both premature SSPC populations exhibited apoptotic signaling pathway activation and decreased mechanosensation.Physical exercise reversed the effects of Z24depletion on cellular apoptosis,extracellular matrix expression and bone mass.This study identified two populations of SSPCs that are responsible for premature aging-related bone loss.The impairment of mechanosensation in Z24-deficient SSPCs provides new insight into how physical exercise can be used to prevent bone aging.
基金partially supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number R01AR062908(to MEI),R01AR056837(to MI),R01AR073181(to SO),and R21AR077654(to SO)the departmental fund of the University of Maryland(to MI,ME-I)。
文摘Longitudinal bone growth relies on endochondral ossification in the cartilaginous growth plate,where chondrocytes accumulate and synthesize the matrix scaffold that is replaced by bone.The chondroprogenitors in the resting zone maintain the continuous turnover of chondrocytes in the growth plate.Malnutrition is a leading cause of growth retardation in children;however,after recovery from nutrient deprivation,bone growth is accelerated beyond the normal rate,a phenomenon termed catch-up growth.Although nutritional status is a known regulator of long bone growth,it is largely unknown whether and how chondroprogenitor cells respond to deviations in nutrient availability.Here,using fate-mapping analysis in Axin2CreERT2 mice,we showed that dietary restriction increased the number of Axin2+chondroprogenitors in the resting zone and simultaneously inhibited their differentiation.Once nutrient deficiency was resolved,the accumulated chondroprogenitor cells immediately restarted differentiation and formed chondrocyte columns,contributing to accelerated growth.Furthermore,we showed that nutrient deprivation reduced the level of phosphorylated Akt in the resting zone and that exogenous IGF-1 restored the phosphorylated Akt level and stimulated differentiation of the pooled chondroprogenitors,decreasing their numbers.Our study of Axin2CreERT2 revealed that nutrient availability regulates the balance between accumulation and differentiation of chondroprogenitors in the growth plate and further demonstrated that IGF-1 partially mediates this regulation by promoting the committed differentiation of chondroprogenitor cells.
基金funded by the NIH/NIAMS (R01 AR070773,R01 AR068316,R01 DE031028,R21 AR078919)USAMRAA through the Peer Reviewed Medical Research Program (W81XWH-18-1-0121,W81XWH-18-1-0336)+4 种基金the Peer Reviewed Orthopaedic Research Program (W81XWH-20-10795)Broad Agency Announcement (W81XWH-1810613)the American Cancer Society (Research Scholar Grant,RSG-18-027-01-CSM)the Maryland Stem Cell Research Foundationfunded by the NIH (R01 AR079171,R01 AR078324,and R01 AR071379)。
文摘Heterotopic ossification(HO)is a pathological process resulting in aberrant bone formation and often involves synovial lined tissues.During this process,mesenchymal progenitor cells undergo endochondral ossification.Nonetheless,the specific cell phenotypes and mechanisms driving this process are not well understood,in part due to the high degree of heterogeneity of the progenitor cells involved.Here,using a combination of lineage tracing and single-cell RNA sequencing(sc RNA-seq),we investigated the extent to which synovial/tendon sheath progenitor cells contribute to heterotopic bone formation.For this purpose,Tppp3(tubulin polymerization-promoting protein family member 3)-inducible reporter mice were used in combination with either Scx(Scleraxis)or Pdgfra(platelet derived growth factor receptor alpha)reporter mice.Both tendon injury-and arthroplasty-induced mouse experimental HO models were utilized.Sc RNA-seq of tendon-associated traumatic HO suggested that Tppp3 is an early progenitor cell marker for either tendon or osteochondral cells.Upon HO induction,Tppp3 reporter^(+)cells expanded in number and partially contributed to cartilage and bone formation in either tendon-or joint-associated HO.In double reporter animals,both Pdgfra^(+)Tppp3^(+)and Pdgfra^(+)Tppp3^(-) progenitor cells gave rise to HO-associated cartilage.Finally,analysis of human samples showed a substantial population of TPPP3^(-) expressing cells overlapping with osteogenic markers in areas of heterotopic bone.Overall,these data demonstrate that synovial/tendon sheath progenitor cells undergo aberrant osteochondral differentiation and contribute to HO after trauma.
基金supported by the National Natural Science Foundations of China 82230030 and 81871492(Y.L.),82201020(Y.W),and 82100980(S.S.J)the Beijing Natural Science Foundation JL23002(Y.L.)and 7214305(S.S.J)+6 种基金the Beijing International Science and Technology Cooperation Project Z221100002722003(Y.L.)the Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.)Ten-Thousand Talents Program QNBJ2019-2(Y.L.)the Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001(Y.L.)Beijing Nova Program Z211100002121043(Y.W.)China National Postdoctoral Program for Innovative Talents BX2021022(Y.W.),BX20200020(S.S.J)China Postdoctoral Science Foundation 2021M700281(Y.W.)。
文摘Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.
基金Supported by the National Key Research and Development Program of China(No.2018YFA0107302)the Natural Science Foundation of Chongqing,China(No.cstc2021jcyj-msxm X0437)。
文摘AIM:To explore whether the subretinal transplantation of retinal progenitor cells from human embryonic stem cell-derived retinal organoid(h ERO-RPCs)could promote Müller glia dedifferentiation and transdifferentiation,thus improving visual function and delaying retinal degenerative progression.METHODS:h ERO-RPCs were subretinally transplanted into Royal College of Surgeons(RCS)rats.Electroretinography(ERG)recording was performed at 4 and 8wk postoperation to assess retinal function.Using immunofluorescence,the changes in outer nuclear layer(ONL)thickness and retinal Müller glia were explored at 2,4,and 8wk postoperation.To verify the effect of h ERO-RPCs on Müller glia in vitro,we cocultured h ERO-RPCs with Müller glia with a Transwell system.After coculture,Ki67 staining and quantitative polymerase chain reaction(q PCR)were performed to measure the proliferation and m RNA levels of Müller glia respectively.Cell migration experiment was used to detect the effect of h ERO-RPCs on Müller glial migration.Comparisons between two groups were performed by the unpaired Student’s t-test,and comparisons among multiple groups were made with one-way ANOVA followed by Tukey’s multiple comparison test.RESULTS:The visual function and ONL thickness of RCS rats were significantly improved by transplantation of h ERO-RPCs at 4 and 8wk postoperation.In addition to inhibiting gliosis at 4 and 8wk postoperation,h ERO-RPCs significantly increased the expression of dedifferentiation-associated transcriptional factor in Müller glia and promoted the migration at 2,4 and 8wk postoperation,but not the transdifferentiation of these cells in RCS rats.In vitro,using the Transwell system,we found that h ERO-RPCs promoted the proliferation and migration of primary rat Müller glia and induced their dedifferentiation at the m RNA level.CONCLUSION:These results show that h ERO-RPCs might promote early dedifferentiation of Müller glia,which may provide novel insights into the mechanisms of stem cell therapy and Müller glial reprogramming,contributing to the development of novel therapies for retinal degeneration disorders.
基金Supported by the National Nature Science Foundation of China(No.82070937,No.81870640,No.82000923).
文摘AIM:To observe the effect of low oxygen concentration on the neural retina in human induced pluripotent stem cell(hiPSC)-derived retinal organoids(ROs).METHODS:The hiPSC and a three-dimensional culture method were used for the experiments.Generated embryoid bodies(EBs)were randomly and equally divided into hypoxic and normoxic groups.Photographs of the EBs were taken on days 38,45,and 52,and the corresponding volume of EBs was calculated.Simultaneously,samples were collected at these three timepoints,followed by fixation,sectioning,and immunofluorescence.RESULTS:The proportion of Ki67-positive proliferating cells increased steadily on day 38;this proliferationpromoting effect tended to increase tissue density rather than tissue volume.On days 45 and 52,the two groups had relatively similar ratios of Ki67-positive cells.Further immunofluorescence analysis showed that the ratio of SOX2-positive cells significantly increased within the neural retina on day 52(P<0.05).In contrast,the percentage of PAX6-and CHX10-positive cells significantly decreased following hypoxia treatment at all three timepoints(P<0.01),except for CHX10 at day 45(P>0.05).Moreover,the proportion of PAX6-/TUJ1+cells within the neural retinas increased considerably(P<0.01,<0.05,<0.05 respectively).CONCLUSION:Low oxygen promotes stemness and proliferation of neural retinas,suggesting that hypoxic conditions can enlarge the retinal progenitor cell pool in hiPSC-derived ROs.
基金Supported by the Natural Science Foundation of Anhui Province,No.2008085MH251Key Research and Development Project of Anhui Province,No.202004J07020037+1 种基金Anhui Provincial Institute of Translational Medicine,No.2021zhyx-C19National Undergraduate Innovation and Entrepreneurship training program,No.202010366016。
文摘Different fates of neural stem/progenitor cells(NSPCs)and their progeny are determined by the gene regulatory network,where a chromatin-remodeling complex affects synergy with other regulators.Here,we review recent research progress indicating that the BRG1/BRM-associated factor(BAF)complex plays an important role in NSPCs during neural development and neural developmental disorders.Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation,which can also lead to various diseases in humans.We discussed BAF complex subunits and their main characteristics in NSPCs.With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs,we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs.Considering recent progress in these research areas,we suggest that three approaches should be used in investigations in the near future.Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders.More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.
基金Supported by the Guizhou Science and Technology Department,No.Qian-Ke-He[2018]1097the National Natural Science Foundation of China,No.81560056+2 种基金Program for Training Outstanding Young Scientific and Technological Talents of Guizhou Province,No.Qian Kehe Platform Talents[2019]5662Program for the Scientific Activities of Selected Returned Overseas Professionals in Guizhou Province,No.Grant Qian-Ren[2018]0003Scientific and Technological Platform and Talent Team Project of Guizhou Province,No.Qian Kehe Platform Talents[2017]5405.
文摘Vascular injury is a frequent pathology in coronary artery disease.To repair the vasculature,scientists have found that endothelial progenitor cells(EPCs)have excellent properties associated with angiogenesis.Over time,research on EPCs has made encouraging progress regardless of pathology or clinical technology.This review focuses on the origins and cell markers of EPCs,and the connection between EPCs and coronary artery disease.In addition,we summarized various studies of EPC-capturing stents and EPC infusion therapy,and aim to learn from past technology to predict the future.
文摘Most hematopoietic stem progenitor cells (HSPCs) reside in bone marrow (BM), but a small amount of HSPCs have been found to circulate between BM and tissues through blood and lymph. Several lines of evidence suggest that sphingosine-1-phosphate (S1P) gradient triggers HSPC egression to blood circulation after mobilization from BM stem cell niches. Stem cells also visit certain tissues. After a temporary 36 h short stay in local tissues, HSPCs go to lymph in response to S1P gradient between lymph and tissue and eventually enter the blood circulation. S1P also has a role in the guidance of the primitive HSPCs homing to BM in vivo, as S1P analogue FTY720 treatment can improve HSPC BM homing and engraftment. In stress conditions, various stem cells or progenitor cells can be attracted to local injured tissues and participate in local tissue cell differentiation and tissue rebuilding through modulation the expression level of S1P1, S1P2 or S1P3 receptors. Hence, S1P is important for stem cells circulation in blood system to accomplish its role in body surveillance and injury recovery.
基金Supported by The National Medical Research Council,Singa-pore,No.NMRC/NIG/1038/2010the National University Health System Clinician Scientist Program(NCSP)from the Cli-nician Scientist Unit,Yong Loo Lin School of Medicine,National University of Singapore
文摘Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells(EPCs) are derived from hematopoietic stem cells and are capable of forming new blood vessels through a process of vas-culogenesis. There are studies which report correlations between circulating EPCs and cardiovascular risk fac-tors. There are also studies on how pharmacotherapies may influence levels of circulating EPCs. In this review, we discuss the potential role of endothelial progenitor cells as both diagnostic and prognostic biomarkers. In addition, we look at the interaction between cardio-vascular pharmacotherapies and endothelial progenitor cells. We also discuss how EPCs can be used directly and indirectly as a therapeutic agent. Finally, we evalu-ate the challenges facing EPC research and how these may be overcome.
文摘Circulating bone-marrow-derived cells,named endothelial progenitor cells(EPCs),are capable of maintaining,generating,and replacing terminally differentiated cells within their own specific tissue as a consequence of physiological cell turnover or tissue damage due to injury.Endothelium maintenance and restoration of normal endothelial cell function is guaranteed by a complex physiological procedure in which EPCs play a significant role.Decreased number of peripheral blood EPCs has been associated with endothelial dysfunction and high cardiovascular risk.In this review,we initially report current knowledge with regard to the role of EPCs in healthy subjects and the clinical value of EPCs in different disease populations such as arterial hypertension,obstructive sleep-apnea syndrome,obesity,diabetes mellitus,peripheral arterial disease,coronary artery disease,pulmonary hypertension,and heart failure.Recent studies have introduced the novel concept that physical activity,either performed as a single exercise session or performed as part of an exercise training program,results in a significant increase of circulating EPCs.In the second part of this review we provide preliminary evidence from recent studies investigating the effects of acute and long-term exercise in healthy subjects and athletes as well as in disease populations.
