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How mesenchymal stem cell cotransplantation with hematopoietic stem cells can improve engraftment in animal models

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World Journal of Stem Cells 2022年第8期14卷 658-679页

作者： Murilo Montenegro Garrigós Fernando Anselmo de Oliveira Mariana Penteado Nucci Leopoldo Penteado Nucci Arielly da Hora Alves Olivia Furiama Metropolo Dias Lionel Fernel Gamarra Hospital Israelita Albert Einstein São Paulo 05652-900São PauloBrazil Instituto de Química Universidade de São PauloSão Paulo 05508-900São PauloBrazil LIM44-Hospital das Clínicas Faculdade Medicina da Universidade de São PauloSão Paulo 05403-000Brazil Centro Universitário do Planalto Central Área Especial para Industria nº02 Setor Leste-Gama-DFBrasília 72445-020Distrito FederalBrazil

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 *** 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 *** To analyze HSC and MSC characteristics and their interactions through cotransplantation in murine *** 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 *** excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than *** PubMed,we initially identified 555 articles and after selection,only 12 were *** Scopus,2010 were identified,and six were left after the screening and eligibility *** Of the 2565 articles found in the databases,only 18 original studies met the eligibility *** 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 ***,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 *** were characterized prior to administration in almost every *** recipient used was mostly immunodeficient mice submitted to low-dose irradiation or *** main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism,followed by hematopoietic reconstitution and survival anal

关键词： Mesenchymal stem cells Hematopoietic stem cells Bone marrow transplantation Cotransplantation Hematopoietic reconstitution engraftment

Long-term engraftment of p18^(INK4C)-deficient hematopoietic stem cells is enhanced in the sublethally-irradiated recipients

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Science China(Life Sciences) 2006年第4期49卷 390-394页

作者： HUANG Paulina SHIELDS Donna Hillman Cancer Center University of Pittsburgh Pittsburgh USA

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.

关键词： p18INK4C (p18), hematopoietic stem cells (HSCs), engraftment efficiency, sublethal irradiation.

Against all odds: The road to success in the development of human immune reconstitution mice

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ANIMAL MODELS AND EXPERIMENTAL MEDICINE 2024年第4期7卷 460-470页

作者： Bin, Yixiao Ren, Jing Zhang, Haowei Zhang, Tianjiao Liu, Peijuan Xin, Zhiqian Yang, Haijiao Feng, Zhuan Chen, Zhinan Zhang, Hai Shaanxi Univ Chinese Med Sch Basic Med Sci Xianyang Peoples R China Fourth Mil Med Univ Natl Translat Sci Ctr Mol Med Dept Cell Biol Xian Peoples R China Fourth Mil Med Univ State Key Lab New Targets Discovery & Drug Dev Maj Xian Peoples R China Fourth Mil Med Univ Sch Publ Hlth Dept Occupat & Environm Hlth Xian Peoples R China Fourth Mil Med Univ Sch Publ Hlth Minist Educ Key Lab Hazard Assessment & Control Special Operat Xian Peoples R China

The mouse genome has a high degree of homology with the human genome, and its physiological, biochemical, and developmental regulation mechanisms are similar to those of humans; therefore, mice are widely used as experimental animals. However, it is undeniable that interspecies differences between humans and mice can lead to experimental errors. The differences in the immune system have become an important factor limiting current immunological research. The application of immunodeficient mice provides a possible solution to these problems. By transplanting human immune cells or tissues, such as peripheral blood mononuclear cells or hematopoietic stem cells, into immunodeficient mice, a human immune system can be reconstituted in the mouse body, and the engrafted immune cells can elicit human-specific immune responses. Researchers have been actively exploring the development and differentiation conditions of host recipient animals and grafts in order to achieve better immune reconstitution. Through genetic engineering methods, immunodeficient mice can be further modified to provide a favorable developmental and differentiation microenvironment for the grafts. From initially only being able to reconstruct single T lymphocyte lineages, it is now possible to reconstruct lymphoid and myeloid cells, providing important research tools for immunology-related studies. In this review, we compare the differences in immune systems of humans and mice, describe the development history of human immune reconstitution from the perspectives of immunodeficient mice and grafts, and discuss the latest advances in enhancing the efficiency of human immune cell reconstitution, aiming to provide important references for immunological related researches. Over recent decades, researchers have been actively exploring the development and differentiation conditions of host recipient animals and grafts in order to achieve better immune reconstitution. The human immune system can be reconstituted

关键词： hematopoietic stem cell human immune reconstitution immune response immunodeficient mice peripheral blood mononuclear cell transplantation HEMATOPOIETIC STEM-CELLS SEVERE COMBINED IMMUNODEFICIENCY MOUSE MODEL NITRIC-OXIDE BONE-MARROW SCID MOUSE CLASS-I engraftment SYSTEM DEFICIENT

Cell-based therapeutic strategies for treatment of spinocerebellar ataxias:an update

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Neural Regeneration Research 2023年第6期18卷 1203-1212页

作者： Joana Sofia Correia Sara Duarte-Silva António JoséSalgado Patrícia Maciel Life and Health Sciences Research Institute(ICVS) School of MedicineUniversity of MinhoBragaPortugal ICVS/3B’s–PT Government Associate Laboratory BragaGuimarãesPortugal

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 *** features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy *** polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous *** ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait *** the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is *** studies have been proposing the use of stem cells as promising tools for central nervous system tissue *** 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 ***,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration ***,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 ***,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still *** 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 *** studies are needed to determine the best route of administration,without neglec

关键词： cell transplantation engraftment induced pluripotent stem cells mesenchymal stem cells neural progenitor cells neuroprotection polyglutamine spinocerebellar ataxias secretome spinocerebellar ataxia stem cell therapy

Impact of T cells on hematopoietic stem and progenitor cell function:Good guys or bad guys?

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World Journal of Stem Cells 2017年第2期9卷 37-44页

作者： Sulima Geerman Martijn A Nolte Sanquin Research Department of HematopoiesisLandsteiner LaboratoryAcademic Medical CentreUniversity of Amsterdam1066CX AmsterdamThe Netherlands

When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that are the major drivers of graft-vs-host disease(Gv HD). The risk for Gv HD can simply be reduced by the removal of these T cells from the graft. However, this is not always desirable, as this procedure also decreases the engraftment of the transplanted HSPCs and, if applicable, a graft-vs-tumor effect. This poses an important conundrum in the field: T cells act as a double-edged sword upon allogeneic HSPC transplantation, as they support engraftment of HSPCs and provide anti-tumor activity, but can also cause Gv HD. It has recently been suggested that T cells also enhance the engraftment of autologous HSPCs, thus supporting the notion that T cells and HSPCs have an important functional interaction that is highly beneficial, in particular during transplantation. The underlying reason on why and how T cells contribute to HSPC engraftment is still poorly understood. Therefore, we evaluate in this review the studies that have examined the role of T cells during HSPC transplantation and the possible mechanisms involved in their supporting function. Understanding the underlying cellular and molecular mechanisms can provide new insight into improving HSPC engraftment and thus lower the number of HSPCs required during transplantation. Moreover, it could provide new avenues to limit the development of severe Gv HD, thus making HSPC transplantations more efficient and ultimately safer.

关键词： Hematopoietic stem cells Hematopoietic stem and progenitor cells CD8 T cells Transplantation engraftment Memory T cells Facilitating cells Bone marrow

APPLICATION OF TWO-COLOR INTERPHASE FISH USING SEX PROBE IN ALLOGENEIC STEM CELL TRANSPLANTATION

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Chinese Journal of Cancer Research 2002年第1期14卷 73-75页

作者：曾慧兰李建勇朱康儿薛永权李杨秋刘晓力过宇 First Affiliated Hospital Medical College Jinan University Guangzhou 510630 First Affiliated Hospital Nanjing University Nanjing 210008 Institution of Hematology of Jiangsu Province Suzhou 215007 Nanfang Hospital First Military Medical University Guangzhou 510515

Objective: To evaluate the significance of two-color interphase fluorescence in situ hybridization (FISH) using X and Y centromere probe in the engraftment estimation and minimal residual disease (MRD) monitoring after allogeneic stem cell transplantation (alloSCT). Methods: Samples from 12 cases patients in different periods after alloSCT were detected by interphase FISH. Results: All of the 12 patients were proved to obtain engraftment 22–35 days after alloSCT. While traditional karyotype showed as 100%XX or 100%XY invariably, FISH showed different percentages of donor original sex chromosome. Conclusion: Two-color interphase FISH is a more sensitive and simple test for engraftment evaluation and MRD monitoring post SCT, though, it can not entirely replace traditional karyotype analysis and gene detection by RT-PCR.

关键词： Allogeneic stem cell transplantation Interphase fluorescence in situ hybridization engraftment Minimal residual disease

Considerations for hematopoietic stem cell transplantation in primary immunodeficiency disorders

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World Journal of Transplantation 2019年第3期9卷 48-57页

作者： Tatyana Gavrilova Division of Allergy and Immunology Montefiore Medical Center

Primary immunodeficiency disorders (PIDs) result from inborn errors in *** to infections and oftentimes severe autoimmunity pose life-threatening risks to patients with these *** cell transplant (HCT) remains the only curative option for *** combined immunodeficiency disorders (SCID) most commonly present at the time of birth and typically require emergent HCT in the first few weeks of *** poses an unusual challenge for *** source and conditioning regimen often impact the outcome of immune reconstitution after HCT in *** use of matched or unmatched, as well as related versus unrelated donor has resulted in variable outcomes for different subsets of ***, there is significant variability in the success of engraftment even for a single patient’s lymphocyte *** certain cell lines do well without a conditioning regimen, others will not reconstitute unless conditioning is *** decision to proceed with a conditioning regimen in an already immunocompromised host is further complicated by the fact that alkylating agents should be avoided in radiosensitive *** manuscript reviews some of the unique elements of HCT in PIDs and evidence-based approaches to transplant in patients with these rare and challenging disorders.

关键词： Primary immunodeficiency disorders Hematopoietic stem cell transplant Autoimmunity Conditioning regimens engraftment

Impact of conditioning regimen on peripheral blood hematopoietic cell transplant

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World Journal of Clinical Oncology 2019年第2期10卷 86-97页

作者： Michael Burns Anurag K Singh Carrie C Hoefer Yali Zhang Paul K Wallace George L Chen Alexis Platek Timothy B Winslow Austin J Iovoli Christopher Choi Maureen Ross Philip L McCarthy Theresa Hahn Department of Medicine Roswell Park Comprehensive Cancer Center Department of Radiation Medicine Roswell Park Comprehensive Cancer Center Department of Flow Cytometry Roswell Park Comprehensive Cancer Center Center for Immunotherapy Roswell Park Comprehensive Cancer Center

AIM To investigate infused hematopoietic cell doses and their interaction with conditioning regimen intensity +/-total body irradiation(TBI) on outcomes after peripheral blood hematopoietic cell transplant(PBHCT).METHODS Our retrospective cohort included 247 patients receiving a first, T-replete, human leukocyte antigen-matched allogeneic PBHCT and treated between 2001 and2012. Correlations were calculated using the Pearson product-moment correlation coefficient. Overall survival and progression free survival curves were generated using the Kaplan-Meier method and compared using the log-rank *** Neutrophil engraftment was significantly faster after reduced intensity TBI based conditioning [reduced intensity conditioning(RIC) + TBI] and > 4 × 10~6 CD34+cells/kg infused. A higher total nucleated cell dose led to a higher incidence of grade II-IV acute graft-versus-host disease in the myeloablative + TBI regimen group(P = 0.03), but no significant difference in grade III-IV graft-versus-host disease. A higher total nucleated cell dose was also associated with increased incidence of moderate/severe chronic graft-versus-host disease, regardless ofconditioning regimen. Overall and progression-free survival were significantly better in patients with a RIC + TBI regimen and total nucleated cell dose > 8 ×10~8/kg(3 years, overall survival: 70% vs 38%, P = 0.02, 3 years, progression free survival: 64% vs 38%, P = 0.02).CONCLUSION TBI and conditioning intensity may alter the relationship between infused cell doses and outcomes after PBHCT. Immune cell subsets may predict improved survival after unmanipulated PBHCT.

关键词： Total body radiation Peripheral blood hematopoietic cell transplant Total nucleated dose Neutrophil engraftment Graft-versus-host-disease

Xenogeneic hepatic progenitor cell transplantation ameliorate CCl_4 /partial hepatectomy-induced rat acute liver failure

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Journal of Medical Colleges of PLA(China) 2013年第6期28卷 355-367页

作者： WAN Zhen Lü Yi ZHANG Xiaogang ZHENG Xing-long WU Wanquan MA Jia WANG Haohua Department of Hepatobiliary Surgery the First Affiliated Hospital Medical School of Xi'an Jiaotong University Institute of Advanced Surgical Techniques and Tissue Engineering Research Xi'an Jiaotong University

Objective： Hepatic progenitor cell transplantation has shed light on the treatment of liver failure. The present study was designed to evaluate whether xenogeneic liver epithelial progenitor cells （LEPCs） transplantation could promote liver recovery in a rat model of acute liver failure. The engraftment and hepatocytic differentiation of transplanted hepatic progenitor cells in the rat spleen was also investigated. Methods： LEPCs were propagated in vitro for long and transduced with lentiviral vector carrying mCherry gene. Intraperitoneal injection of CC14 followed by 2/3 partial hepatectomy three days later were used to establish rat models of acute liver failure. Rats were intrasplenically injected with mCherry modified LEPCs （n=20, 1× 107 cells/0.5 mL） or the same volume of medium （n=20）. Serum liver enzymes （ALT, AST） and liver histology were evaluated for 21 days after transplantation. The engraftment of transplanted LEPCs in the spleens was tested by polymerase chain reaction （PCR） amplification targeting mCherry gene. The differentiation into hepatocytic lineage of transplanted LEPCs was investigated usingimmunohistochemistry staining against Alb. Results： LEPCs were effectively transduced with lentiviral vector showing a transduction efficiency of 90%. Compared with control, cell-injected group displayed significantly lower levels of ALT and AST （P〈0.05） and better histological features including less swelling change and hepatocyte death. PCR amplification of mCherry sequences confirmed the engraftment of LEPCs in the spleens. Alb-positive cells first appeared 5 days after cell transplantation and the number of Alb-positive cells increased substantially （P〈0.05）, which revealed the hepatocytic differentiation process Conclusion： Xenogeneic hepatic progenitor cells can engraft and differentiate into hepatocytes in the splenic parenchyma. Intrasplenic delivery of hepatic progenitor cells ameliorates CCh/partial hepatectomy-induced liver injury in rats

关键词： Acute liver failure engraftment Hepatic progenitor cells Intrasplenic transplantation