Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans.


:Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells1. Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood cell production caused by congenital or acquired disorders2-9. However, due to methodological and ethical constraints that have limited the study of human HSPC primarily to in vitro assays10 or xenotransplantation models11,12, the in vivo activity of HSPC has to date remained relatively unexplored in humans13-16. Here we report a comprehensive study of the frequencies, dynamics and output of seven HSPC subtypes in humans that was performed by tracking 148,093 individual clones in six patients treated with lentiviral gene therapy using autologous HSPC transplantation and followed for up to 5 years. We discovered that primitive multipotent progenitor and hematopoietic stem cell (HSC) populations have distinct roles during the initial reconstitution after transplant, compared with subsequent steady-state phases. Furthermore, we showed that a fraction of in vitro-activated HSC are resilient and undergo a defined delayed activation period upon transplant. Finally, our data support the concept that early lymphoid-biased progenitors might be capable of long-term survival, such that they can be maintained independently of their continuous production from HSC. Overall, this study provides comprehensive data on HSPC dynamics after autologous transplantation and gene therapy in humans.


Nat Med


Nature medicine


Scala S,Basso-Ricci L,Dionisio F,Pellin D,Giannelli S,Salerio FA,Leonardelli L,Cicalese MP,Ferrua F,Aiuti A,Biasco L




Has Abstract


2018-11-01 00:00:00














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    authors: Wagar LE,Salahudeen A,Constantz CM,Wendel BS,Lyons MM,Mallajosyula V,Jatt LP,Adamska JZ,Blum LK,Gupta N,Jackson KJL,Yang F,Röltgen K,Roskin KM,Blaine KM,Meister KD,Ahmad IN,Cortese M,Dora EG,Tucker SN,Sperling AI

    更新日期:2021-01-01 00:00:00

  • Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment.

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    journal_title:Nature medicine

    pub_type: 杂志文章


    authors: Hattori K,Heissig B,Wu Y,Dias S,Tejada R,Ferris B,Hicklin DJ,Zhu Z,Bohlen P,Witte L,Hendrikx J,Hackett NR,Crystal RG,Moore MA,Werb Z,Lyden D,Rafii S

    更新日期:2002-08-01 00:00:00

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    pub_type: 杂志文章


    authors: Brooks-Kayal AR,Shumate MD,Jin H,Rikhter TY,Coulter DA

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    abstract::Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematu...

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    pub_type: 杂志文章


    authors: Romani L,Oikonomou V,Moretti S,Iannitti RG,D'Adamo MC,Villella VR,Pariano M,Sforna L,Borghi M,Bellet MM,Fallarino F,Pallotta MT,Servillo G,Ferrari E,Puccetti P,Kroemer G,Pessia M,Maiuri L,Goldstein AL,Garaci E

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    abstract::Sympathetic innervation is critical for effective cardiac function. However, the developmental and regulatory mechanisms determining the density and patterning of cardiac sympathetic innervation remain unclear, as does the role of this innervation in arrhythmogenesis. Here we show that a neural chemorepellent, Sema3a,...

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    authors: Ieda M,Kanazawa H,Kimura K,Hattori F,Ieda Y,Taniguchi M,Lee JK,Matsumura K,Tomita Y,Miyoshi S,Shimoda K,Makino S,Sano M,Kodama I,Ogawa S,Fukuda K

    更新日期:2007-05-01 00:00:00

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    abstract::To better understand genetic alterations in oral premalignant lesions, we examined 84 oral leukoplakia samples from 37 patients who had been enrolled in a chemoprevention trial. The samples were analyzed for two microsatellite markers located at chromosomes 9p21 and 3p14. Loss of heterozygosity (LOH) at either or both...

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    authors: Mao L,Lee JS,Fan YH,Ro JY,Batsakis JG,Lippman S,Hittelman W,Hong WK

    更新日期:1996-06-01 00:00:00

  • α-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria.

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    authors: Zee T,Bose N,Zee J,Beck JN,Yang S,Parihar J,Yang M,Damodar S,Hall D,O'Leary MN,Ramanathan A,Gerona RR,Killilea DW,Chi T,Tischfield J,Sahota A,Kahn A,Stoller ML,Kapahi P

    更新日期:2017-03-01 00:00:00

  • Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein.

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    authors: Malhotra R,Wormald MR,Rudd PM,Fischer PB,Dwek RA,Sim RB

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    authors: Wong GS,Zhou J,Bin Liu J,Wu Z,Xu X,Li T,Xu D,Schumacher SE,Puschhof J,McFarland J,Zou C,Dulak A,Henderson L,Xu P,O'Day E,Rendak R,Liao WL,Cecchi F,Hembrough T,Schwartz S,Szeto C,Rustgi AK,Wong KK,Diehl JA,

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