Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig’s disease in the United States,Charcot’s disease in France,and motor neuron disease in the UK.The loss of motor n...Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig’s disease in the United States,Charcot’s disease in France,and motor neuron disease in the UK.The loss of motor neurons causes muscle wasting,paralysis,and eventually death,which is commonly related to respiratory failure,within 3-5 years after onset of the disease.Although there are a limited number of drugs approved for amyotrophic lateral sclerosis,they have had little success at treating the associated symptoms,and they cannot reverse the course of motor neuron degeneration.Thus,there is still a lack of effective treatment for this debilitating neurodegenerative disorder.Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers,particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons.Stem cell therapies may also be able to re-establish the motor control of voluntary muscles.Here,we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis.We focus on MN progenitor cells derived from fetal central nervous system tissue,embryonic stem cells,and induced pluripotent stem cells.In our recent studies,we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well,differentiate into motor neurons,and extend axons into the host white matter,not only in the rostrocaudal direction,but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord.Furthermore,the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis,particularly as a variety of stem cell derivatives,including induced pluripotent stem cells,are being considered for clinical trials for various diseases.展开更多
Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein w...Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein with death domain(FADD),or caspase-8,but the mechanism is largely unknown.Here,we report that the DNA-dependent activator of IFN regulatory factors(ZBP1,also known as DAI)is required for both type Ⅰ(β)and type Ⅱ(γ)IFN-induced necroptosis.We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1,FADD,or Caspase-8 was genetically deleted,confirming the antinecroptotic role of these proteins in IFN signaling.We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1,an IFN-stimulated gene(ISG)product,as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells.The N-terminal domain(ND)of ZBP1 is important for ZBP1–ZBP1 homointeraction,and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis.The antinecroptotic function of RIPK1,FADD,and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3,since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated.ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant,as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome(SIRS)induced by TNF+IFN-γ.展开更多
基金supported by the Stem Cell and Translation National Key Project(No.2016YFA0101403,to ZC)the National Natural Science Foundation of China(Nos.81973351,81661130160,81422014,81561138004,all to ZC)+7 种基金the Beijing Municipal Natural Science Foundation(No.5142005,to ZC)Beijing Talents Foundation(No.2017000021223TD03,to ZC)the Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-Year Plan(No.CIT&TCD20180333,to ZC)the Beijing Medical System High Level Talent Award(No.2015-3-063,to ZC)Beijing Municipal Health Commission Fund(No.PXM2020_026283_000005)Beijing One Hundred,Thousand,and Ten Thousand Talents Fund(No.2018A03,to ZC)the Royal Society-Newton Advanced Fellowship(No.NA150482,to ZC)the USA Veterans Administration(No.I01 RX002264-01A2,to PL).
文摘Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig’s disease in the United States,Charcot’s disease in France,and motor neuron disease in the UK.The loss of motor neurons causes muscle wasting,paralysis,and eventually death,which is commonly related to respiratory failure,within 3-5 years after onset of the disease.Although there are a limited number of drugs approved for amyotrophic lateral sclerosis,they have had little success at treating the associated symptoms,and they cannot reverse the course of motor neuron degeneration.Thus,there is still a lack of effective treatment for this debilitating neurodegenerative disorder.Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers,particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons.Stem cell therapies may also be able to re-establish the motor control of voluntary muscles.Here,we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis.We focus on MN progenitor cells derived from fetal central nervous system tissue,embryonic stem cells,and induced pluripotent stem cells.In our recent studies,we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well,differentiate into motor neurons,and extend axons into the host white matter,not only in the rostrocaudal direction,but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord.Furthermore,the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis,particularly as a variety of stem cell derivatives,including induced pluripotent stem cells,are being considered for clinical trials for various diseases.
基金supported by the National Natural Science Foundation of China(81788101)the National Basic Research Program of China(973 Program 2015CB553800)+3 种基金the National Natural Science Foundation of China(31420103910,81630042,31500737,and 31601122)the China Postdoctoral Science Foundation(2018T110638,2017 M620267,and 2015T80680)the 111 Project(B12001)the National Science Foundation of China for Fostering Talents in Basic Research(J1310027).
文摘Interferons(IFNs)play an important role in immunomodulatory and antiviral functions.IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1(RIPK1),Fas-associated protein with death domain(FADD),or caspase-8,but the mechanism is largely unknown.Here,we report that the DNA-dependent activator of IFN regulatory factors(ZBP1,also known as DAI)is required for both type Ⅰ(β)and type Ⅱ(γ)IFN-induced necroptosis.We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1,FADD,or Caspase-8 was genetically deleted,confirming the antinecroptotic role of these proteins in IFN signaling.We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1,an IFN-stimulated gene(ISG)product,as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells.The N-terminal domain(ND)of ZBP1 is important for ZBP1–ZBP1 homointeraction,and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis.The antinecroptotic function of RIPK1,FADD,and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3,since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated.ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant,as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome(SIRS)induced by TNF+IFN-γ.
