Mesenchymal stem cells(MSCs)are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing.MSC-based treatments are generally considered a safe procedure,however,the long-ter...Mesenchymal stem cells(MSCs)are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing.MSC-based treatments are generally considered a safe procedure,however,the long-term results obtained up to now are far from satisfactory.The main causes of these therapeutic limitations are inefficient homing,engraftment,and osteogenic differentiation.Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells.Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation.These strategies could range from a simple modification of the culture conditions,known as cell-preconditioning,to the genetic modification of the cells to avoid cellular senescence.Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation,mainly by the use of bioactive or biomimetic scaffolds,although alternative approaches will also be discussed.This review aims to summarize several of the most recent approaches,providing an up-to-date view of the main developments in MSCbased regenerative techniques.展开更多
The limited capability to regenerate new neurons following injuries of the central neural system（CNS）still remains a major challenge for basic and clinical neuroscience.Neural stem cells（NSCs）could nearly have the...The limited capability to regenerate new neurons following injuries of the central neural system（CNS）still remains a major challenge for basic and clinical neuroscience.Neural stem cells（NSCs）could nearly have the potential to differentiate into all kinds of neural cells in vitro.展开更多
BACKGROUND Bone marrow transplantation(BMT)can be applied to both hematopoietic and nonhematopoietic diseases;nonetheless,it still comes with a number of challenges and limitations that contribute to treatment failure...BACKGROUND Bone marrow transplantation(BMT)can be applied to both hematopoietic and nonhematopoietic diseases;nonetheless,it still comes with a number of challenges and limitations that contribute to treatment failure.Bearing this in mind,a possible way to increase the success rate of BMT would be cotransplantation of mesenchymal stem cells(MSCs)and hematopoietic stem cells(HSCs)to improve the bone marrow niche and secrete molecules that enhance the hematopoietic engraftment.AIM To analyze HSC and MSC characteristics and their interactions through cotransplantation in murine models.METHODS We searched for original articles indexed in PubMed and Scopus during the last decade that used HSC and MSC cotransplantation and in vivo BMT in animal models while evaluating cell engraftment.We excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than English.In PubMed,we initially identified 555 articles and after selection,only 12 were chosen.In Scopus,2010 were identified,and six were left after the screening and eligibility process.RESULTS Of the 2565 articles found in the databases,only 18 original studies met the eligibility criteria.HSC distribution by source showed similar ratios,with human umbilical cord blood or animal bone marrow being administered mainly with a dose of 1×10^(7) cells by intravenous or intrabone routes.However,MSCs had a high prevalence of human donors with a variety of sources(umbilical cord blood,bone marrow,tonsil,adipose tissue or fetal lung),using a lower dose,mainly 106 cells and ranging 104 to 1.5×107 cells,utilizing the same routes.MSCs were characterized prior to administration in almost every experiment.The recipient used was mostly immunodeficient mice submitted to low-dose irradiation or chemotherapy.The main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism,followed by hematopoietic reconstitution and survival analysis.Besides the engraftment,homing and cellularity were also evaluated in some studies.CONCLUSION The preclinical findings validate the potential of MSCs to enable HSC engraftment in vivo in both xenogeneic and allogeneic hematopoietic cell transplantation animal models,in the absence of toxicity.展开更多
Myocardial infarction(MI)results in loss of cardiomyocytes(CM) in the ischemic area of the heart followed by an inflammatory response and replacement of contractile CM with fibrosis.Myocardial fibrosis,a key contribut...Myocardial infarction(MI)results in loss of cardiomyocytes(CM) in the ischemic area of the heart followed by an inflammatory response and replacement of contractile CM with fibrosis.Myocardial fibrosis,a key contributor to cardiac dysfunction after MI,presents as a secondary response to the pathophysiological remodeling of long-standing disease including ischemia,obstruction,and microvascular abnormalities.Cardiac fibroblasts and myofibroblasts are responsible for post-MI remodeling which occurs via regulation of extracellular matrix (ECM),presenting as increased collagenⅠandⅢinto the interstitial and perivascular space.In addition to the pluripotency of stem cells following stem/ progenitor cell transplantation,decreased apoptosis, hypertrophy,and fibrosis in the infarcted heart have been demonstrated.This has made transplantation of progenitor/stem cells a primary research focus in the field of tissue regeneration.Unfortunately,the accumulation of ECM and myofibroblasts in areas of tissue injury presents a barrier that can impair penetration of reparative stem/progenitor cells mobilized from peripheral reservoirs.Therefore,cardiac fibroblast production and degradation of ECM are critical in regulating cardiac remodeling and stem/progenitor cell mobilization.This study used transgenic mice overexpressing adenylyl cyclaseⅥ(AC6) in which collagen synthesis was decreased to determine the role of collagen deposition on the engraftment of iPSC from a tri-cell patch applied to infarcted area after MI.展开更多
Non-myeloablative regimens for host conditioning have been widely used in clinical hematopoietic stem cell transplantation due to their reduced toxicity on the recipients. But a milder conditioning regimen may require...Non-myeloablative regimens for host conditioning have been widely used in clinical hematopoietic stem cell transplantation due to their reduced toxicity on the recipients. But a milder conditioning regimen may require a higher engrafting ability of donor stem cells in competing with endogenous stem cells. Thus, new strategies for enhancing the competitiveness of donor stem cells in non-myeloablative recipients would have important implications for current clinical stem cell trans- plantation. It is known that the absence of p18INK4C (p18) gene can enhance the self-renewal potential of hematopoietic stem cells (HSCs). We applied the approach of competitive bone marrow trans- plantation to evaluate the impact of p18 gene deletion on long-term engraftment of HSCs in sub- lethally irradiated hosts. We found that p18?/? HSCs had a significant advantage over wild-type HSCs during long-term engraftment in the mouse recipients that received a sub-lethal irradiation (5-Gy). The engraftment efficiency of p18?/? HSCs in the sub-lethally irradiated recipients was similar to that in the lethally irradiated (10-Gy) recipients. Our current study demonstrates that enhanced engraftment of donor HSCs in the absence of p18 does not strictly depend on the dose of irradiation used for host conditioning. Therefore, p18 might serve as a potential drug target for increasing the efficacy of stem cell transplant in the patients that are preconditioned with either a myeloablative or non-myeloablative regimen.展开更多
Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding...Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.展开更多
文摘Mesenchymal stem cells(MSCs)are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing.MSC-based treatments are generally considered a safe procedure,however,the long-term results obtained up to now are far from satisfactory.The main causes of these therapeutic limitations are inefficient homing,engraftment,and osteogenic differentiation.Many studies have proposed modifications to improve MSC engraftment and osteogenic differentiation of the transplanted cells.Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation.These strategies could range from a simple modification of the culture conditions,known as cell-preconditioning,to the genetic modification of the cells to avoid cellular senescence.Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation,mainly by the use of bioactive or biomimetic scaffolds,although alternative approaches will also be discussed.This review aims to summarize several of the most recent approaches,providing an up-to-date view of the main developments in MSCbased regenerative techniques.
基金supported by National Program on Key Basic Research Project(973 Programs 2015CB755605)National Natural Science Foundation of China(81471312)
文摘The limited capability to regenerate new neurons following injuries of the central neural system（CNS）still remains a major challenge for basic and clinical neuroscience.Neural stem cells（NSCs）could nearly have the potential to differentiate into all kinds of neural cells in vitro.
基金Supported by CNPq,No.308901/2020,No.400856/2016-6FAPESP,No.2019/21070-3,No.2017/17868-4,No.2016/21470-3+2 种基金SisNANO 2.0/MCTIC,No.442539/2019-3the National Institute of Science and Technology Complex Fluids(INCT-FCx)“Amigos da Oncologia e Hematologia Einstein”AMIGOH.
文摘BACKGROUND Bone marrow transplantation(BMT)can be applied to both hematopoietic and nonhematopoietic diseases;nonetheless,it still comes with a number of challenges and limitations that contribute to treatment failure.Bearing this in mind,a possible way to increase the success rate of BMT would be cotransplantation of mesenchymal stem cells(MSCs)and hematopoietic stem cells(HSCs)to improve the bone marrow niche and secrete molecules that enhance the hematopoietic engraftment.AIM To analyze HSC and MSC characteristics and their interactions through cotransplantation in murine models.METHODS We searched for original articles indexed in PubMed and Scopus during the last decade that used HSC and MSC cotransplantation and in vivo BMT in animal models while evaluating cell engraftment.We excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than English.In PubMed,we initially identified 555 articles and after selection,only 12 were chosen.In Scopus,2010 were identified,and six were left after the screening and eligibility process.RESULTS Of the 2565 articles found in the databases,only 18 original studies met the eligibility criteria.HSC distribution by source showed similar ratios,with human umbilical cord blood or animal bone marrow being administered mainly with a dose of 1×10^(7) cells by intravenous or intrabone routes.However,MSCs had a high prevalence of human donors with a variety of sources(umbilical cord blood,bone marrow,tonsil,adipose tissue or fetal lung),using a lower dose,mainly 106 cells and ranging 104 to 1.5×107 cells,utilizing the same routes.MSCs were characterized prior to administration in almost every experiment.The recipient used was mostly immunodeficient mice submitted to low-dose irradiation or chemotherapy.The main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism,followed by hematopoietic reconstitution and survival analysis.Besides the engraftment,homing and cellularity were also evaluated in some studies.CONCLUSION The preclinical findings validate the potential of MSCs to enable HSC engraftment in vivo in both xenogeneic and allogeneic hematopoietic cell transplantation animal models,in the absence of toxicity.
文摘Myocardial infarction(MI)results in loss of cardiomyocytes(CM) in the ischemic area of the heart followed by an inflammatory response and replacement of contractile CM with fibrosis.Myocardial fibrosis,a key contributor to cardiac dysfunction after MI,presents as a secondary response to the pathophysiological remodeling of long-standing disease including ischemia,obstruction,and microvascular abnormalities.Cardiac fibroblasts and myofibroblasts are responsible for post-MI remodeling which occurs via regulation of extracellular matrix (ECM),presenting as increased collagenⅠandⅢinto the interstitial and perivascular space.In addition to the pluripotency of stem cells following stem/ progenitor cell transplantation,decreased apoptosis, hypertrophy,and fibrosis in the infarcted heart have been demonstrated.This has made transplantation of progenitor/stem cells a primary research focus in the field of tissue regeneration.Unfortunately,the accumulation of ECM and myofibroblasts in areas of tissue injury presents a barrier that can impair penetration of reparative stem/progenitor cells mobilized from peripheral reservoirs.Therefore,cardiac fibroblast production and degradation of ECM are critical in regulating cardiac remodeling and stem/progenitor cell mobilization.This study used transgenic mice overexpressing adenylyl cyclaseⅥ(AC6) in which collagen synthesis was decreased to determine the role of collagen deposition on the engraftment of iPSC from a tri-cell patch applied to infarcted area after MI.
基金partially supported by the Outstanding Award for Chinese Oversea Scholar by the National Natural Science Foundation of China(Grant No.30228011)the General Award of National Natural Science Foundation of China(Grant No.39970709).
文摘Non-myeloablative regimens for host conditioning have been widely used in clinical hematopoietic stem cell transplantation due to their reduced toxicity on the recipients. But a milder conditioning regimen may require a higher engrafting ability of donor stem cells in competing with endogenous stem cells. Thus, new strategies for enhancing the competitiveness of donor stem cells in non-myeloablative recipients would have important implications for current clinical stem cell trans- plantation. It is known that the absence of p18INK4C (p18) gene can enhance the self-renewal potential of hematopoietic stem cells (HSCs). We applied the approach of competitive bone marrow trans- plantation to evaluate the impact of p18 gene deletion on long-term engraftment of HSCs in sub- lethally irradiated hosts. We found that p18?/? HSCs had a significant advantage over wild-type HSCs during long-term engraftment in the mouse recipients that received a sub-lethal irradiation (5-Gy). The engraftment efficiency of p18?/? HSCs in the sub-lethally irradiated recipients was similar to that in the lethally irradiated (10-Gy) recipients. Our current study demonstrates that enhanced engraftment of donor HSCs in the absence of p18 does not strictly depend on the dose of irradiation used for host conditioning. Therefore, p18 might serve as a potential drug target for increasing the efficacy of stem cell transplant in the patients that are preconditioned with either a myeloablative or non-myeloablative regimen.
基金funded by national fundsthrough the Foundation for Science and Technology (FCT)-project UIDB/50026/2020 and UIDP/50026/2020by the National Ataxia Foundation (NAF)
文摘Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.
