scholarly journals Mesenchymal Stem Cell Benefits Observed in Bone Marrow Failure and Acquired Aplastic Anemia

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Vivian Fonseca Gonzaga ◽  
Cristiane Valverde Wenceslau ◽  
Gustavo Sabino Lisboa ◽  
Eduardo Osório Frare ◽  
Irina Kerkis
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Aplastic Anemia ◽  
Blood Cells ◽  
Bone Marrow Failure ◽  
White Blood Cells ◽  
First Line ◽  
Hematopoietic Stem ◽  
Total Bone Marrow ◽  
Hematopoietic Niche

Acquired aplastic anemia (AA) is a type of bone marrow failure (BMF) syndrome characterized by partial or total bone marrow (BM) destruction resulting in peripheral blood (PB) pancytopenia, which is the reduction in the number of red blood cells (RBC) and white blood cells (WBC), as well as platelets (PLT). The first-line treatment option of AA is given by hematopoietic stem cell (HSCs) transplant and/or immunosuppressive (IS) drug administration. Some patients did not respond to the treatment and remain pancytopenic following IS drugs. The studies are in progress to test the efficacy of adoptive cellular therapies as mesenchymal stem cells (MSCs), which confer low immunogenicity and are reliable allogeneic transplants in refractory severe aplastic anemia (SAA) cases. Moreover, bone marrow stromal cells (BMSC) constitute an essential component of the hematopoietic niche, responsible for stimulating and enhancing the proliferation of HSCs by secreting regulatory molecules and cytokines, providing stimulus to natural BM microenvironment for hematopoiesis. This review summarizes scientific evidences of the hematopoiesis improvements after MSC transplant, observed in acquired AA/BMF animal models as well as in patients with acquired AA. Additionally, we discuss the direct and indirect contribution of MSCs to the pathogenesis of acquired AA.

Treatment of Severe Aplastic Anemia with Porcine Anti-Human Lymphocyte Globulin

2020 ◽  
Vol 26 (22) ◽  
pp. 2661-2667
Author(s):  
Qi Lv ◽  
Zhang Huiqin ◽  
Xiao Na ◽  
Liu Chunyan ◽  
Shao Zonghong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
New Product ◽  
Therapeutic Effects ◽  
First Line ◽  
Bone Marrow Failure Syndrome ◽  
Hematopoietic Stem

Aplastic anemia (AA) is a bone marrow failure syndrome characterized by pancytopenia. Decreased numbers of hematopoietic stem cells and impaired bone marrow microenvironment caused by abnormal immune function describe the major pathogenesis of AA. Hematopoietic stem cell transplantation and immunesuppressive therapy are the first-line treatments for AA. Porcine anti-lymphocyte globulin (p-ALG) is a new product developed in China. Several studies have shown that p-ALG exhibited good therapeutic effects in AA.

Hematopoietic Stem Cell Differentiation Pathway in Humans Deduced From the Lineage Diversity of PNH-Type Cells in Patients with Bone Marrow Failure.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1489-1489
Author(s):  
Takamasa Katagiri ◽  
Zhirong Qi ◽  
Yu Kiyu ◽  
Naomi Sugimori ◽  
J. Luis Espinoza ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Bone Marrow Failure ◽  
Stem Cell Differentiation ◽  
Refractory Anemia ◽  
Hematopoietic Stem

Abstract Abstract 1489 Poster Board I-512 The hematopoietic stem cell (HSC) differentiation pathway in humans remains largely unknown due to the lack of an appropriate in vivo assay allowing the growth of HSCs as well as of clonal markers that enable the tracing of their progenies. Small populations of blood cells deficient in glycosylphosphatidylinositol-anchored proteins (GPI-APs) such as CD55 and CD59 are detectable in approximately 50% of patients with aplastic anemia (AA) and 15% of patients with refractory anemia (RA) of myelodysplastic syndrome defined by the FAB classification. Such blood cells with the paroxysmal nocturnal hemoglobinuria (PNH) phenotype (PNH-type cells) are derived from single PIGA mutant HSCs and their fate depends on the proliferation and self-maintenance properties of the individual HSCs that undergo PIG-A mutation by chance (Blood 2008;112:2160, Br J Haematol 2009 in press) Analyses of the PNH-type cells from a large number of patients on the diversity of lineage combination may help clarify the HSC differentiation pathway in humans because PIG-A mutant HSCs in patients with bone marrow failure appear to reflect the kinetics of healthy HSCs. Therefore, different lineages of peripheral blood cells were examined including glycophorin A+ erythrocytes (E), CD11b+ granulocytes (G), CD33+ monocytes (M), CD3+ T cells (T), CD19+ B cells (B), and NKp46+ NK cells (Nk) from 527 patients with AA or RA for the presence of CD55−CD59− cells in E and G, and CD55−CD59−CD48− cells in M,T, B, Nk with high sensitivity flow cytometry. Two hundred and twenty-eight patients (43%) displayed 0.003% to 99.1% PNH-type cells in at least one lineage of cells. The lineage combination patterns of PNH-type cells in these patients included EGM in 71 patients (31%), EGMTBNk in 43 (19%), EG in 37 (16%), T alone 14 (6%), EGMBNk in 11 (5%), G alone in 10 (4%), GM in 10 (4%), EGMNk in 7 (3%), EGMT in 7 (3%), EGMB in 6 (3%), EM in 5 (2%), EGMTB in 3 (1%), EGNk in 1 (0.4%), EGMTNk in 1 (0.4%), GMTB in 1 (0.4%), and GT in 1 (0.4%) (Table). All patterns included G or M, except for 14 patients displaying PNH-type T cells alone. No patients showed TB or TBNk patterns suggestive of the presence of common lymphoid progenitor cells. Peripheral blood specimens from 123 patients of the 228 patients possessing PNH-type cells were examined again after 3 to 10 months and all patients showed the same combination patterns as those revealed by the first examination. PIG-A gene analyses using sorted PNH-type cells from 3 patients revealed the same mutation in G and Nk for 1 patient and in G and T for 2 patients. These findings indicate that human HSCs may take a similar differentiation pathway to that of murine HSCs, the ‘myeloid-based model’ that was recently proposed by Kawamoto et al. (Nature 2008; 10:452), though the cases with PNH-type T cells alone remain to be elucidated. Table. Lineages of cells containing PNH-type cells in patients with AA or RA. The number in the parenthesis denotes the proportion of patients showing each combination pattern in the total patients possessing PNH-type cells. (+ ; presence of PNH-type cells) Disclosures No relevant conflicts of interest to declare.

Comprehensive Analysis of Telomere Biology in Patients with Aplastic Anemia and Hypoplastic Myelodysplastic Syndrome: Further Evidence for a Common Mechanism

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2858-2858
Author(s):  
Anne-Sophie Bouillon ◽  
Monica S. Ferreira ◽  
Benjamin Werner ◽  
Sebastian Hummel ◽  
Jens P. Panse ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Common Mechanism ◽  
Telomere Shortening ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes ◽  
The Individual

Abstract Introduction: Acquired aplastic anemia (AA) is typically characterized by pancytopenia and bone marrow (BM) failure mostly due to an autoimmune attack against the hematopoietic stem cell compartment. Thus, AA patients frequently respond to immunosuppressive therapy (IST). Hypoplastic myelodysplastic syndrome (hMDS) frequently mimics clinical and morphological features of AA and proper clinical discrimination of hMDS from AA sometimes remains difficult. Interestingly, some cases of hMDS respond at least partially to IST and on the other hand, AA can clonally evolve to hMDS. Telomeres shorten with each cell division and telomere length (TL) reflects the replicative potential of somatic cells. Whereas it is proposed that TL can to some degree discriminate hereditary subtypes of bone marrow failure syndromes from classical acquired forms, the role of TL for disease pathogenesis in hMDS remains unclear. In this study, we therefore aimed to investigate accelerated TL shortening as a possible (bio-)marker to distinguish hMDS from AA. Patients and Methods: TL of BM biopsies at diagnosis of 12 patients with hMDS and 15 patients with AA treated in the University Hospital Düsseldorf were analyzed. Mean age was 45.2 years in AA patients and 65.2 years in patients with hMDS. Confocal Q-FISH protocol was used for TL measurement as published previously (Blood, 2012). TL analysis was performed in single-blinded fashion. 28 patients (range 18-80 years) with newly diagnosed M. Hodgkin without BM affection were used as controls for linear regression and calculation of age-adapted TL difference. For the analysis of the data, we made use of a recently developed mathematical model of TL distribution on the stem cell level allowing us to extrapolate mean TL shortening per year (TS/y) based on the individual TL distributions of captured BM biopsies. Results: Using the controls to adjust for age, we found that age-adapted TL was significantly shortened both in patients with AA (median: -2.96 kb, range -4.21 to 0.26, p=0.001) and patients with hMDS (median: -2.26, range -3.85 to -0.64, p=0.005). In direct comparison, telomere shortening was more accelerated in patients with AA as compared to hMDS (p=0.048). Next, we analyzed the TL shortening per year (TS/y) based on the individual telomere distribution. Calculating the extrapolated TL shortening per year (TS/y), we found significant increased TS/y in AA patients (mean±SD: 235,8 bp/y±202,9, p=0.001) and hMDS patients (120,5±41,7 bp/y, p=0.0001) compared to controls (37,5±18,9 bp/y). Interestingly, the extrapolated rate of TS/y remained stable at different ages in hMDS patients as observed in healthy controls. In contrast, TS/y in AA patients showed a strong age-dependence with a maximum of TS/y in patients younger than 30 years (R²=0.42, p=0.008). Finally, we set to test whether TS/y can be used to identify AA or hMDS patients. Using 150 bp TS/y as a cut-off (4-fold the mean of controls), we found significantly more AA patients (10/15, 66.7%) had accelerated TL shortening compared to hMDS (1/12, 8.3% p=0.005). Conclusion: We provide first retrospective data on TL in patients with hMDS using confocal Q-FISH. Age-adapted TL is significantly shorter in patients with AA compared to hMDS. Interestingly, telomere shortening per year is both significantly increased in AA as compared to hMDS patients as well as in both groups compared to controls. The rate of telomere shortening TS/y might represent a new marker in patients with bone marrow failure syndromes that allows to discriminate AA from hMDS patients pending prospective validation. Disclosures No relevant conflicts of interest to declare.

scholarly journals A New Step in Understanding of Fanconi Patients Peripheral Stem Cell Harvesting, a Bridge to Gene Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1970-1970 ◽  
Author(s):  
Jean-Sebastien Diana ◽  
Sandra Manceau ◽  
Thierry Leblanc ◽  
Chloé Couzin ◽  
Alessandra Magnani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Bone Marrow ◽  
Stem Cell ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
White Blood Cells ◽  
Hematopoietic Stem ◽  
Cell Harvesting ◽  
Cd34 Cells

Fanconi anemia (FA) is an inherited disorder, clinically characterized by congenital abnormalities, a fatal progressive bone marrow failure (BMF), and a predisposition to develop malignancies. Gene therapy by infusion of FA-corrected autologous hematopoietic stem cells (HSCs) may offer a potential alternative cure and to get around the problems of the Hematopoietic stem cell transplantation toxicity or the donor restriction. For gene therapy, an adequate number of HSC collected is a key point to a successful engraftment. However, the HSC collection in FA patients implies particular challenges because of their reduced BM stem cells numbers and implies a theorical risk of an inner depletion in stem cell reserve following collection.The main objective of this pilot study was to evaluate the feasibility and the safety of co-administration of G-CSF and plerixafor in patients with FA for the mobilization and collection of peripheral HSC for potential use in a GT trial. We present the results of this open-label phase I/II trial (N°EUDRACT 2014-005264-14) from 4 selected FANCA mutated patients (FA-A) with a weight >10 Kg and an age between 2 to 18 years old. A systematic combination of G-CSF (12μg/kg twice a day) plus plerixafor (Mozobil® 0.240 mg/kg/d ) was used to maximise the CD34+ cells mobilization. CD34+ cells and white blood cells (WBC) blood counts were monitored tightly along the mobilization protocol. No short-term adverse events linked to the mobilization and the collection procedures were observed. The combination of G-CSF and Plerixafor allowed crossing the PB mobilization threshold (≥5 CD34+cells/μL) for 2 patients. Interestingly, CD34+cells were mobilized quickly but transitionally after plerixafor injection. One patient mobilization had more than 100 CD34+cells μ/L with a early peak 2h after injection. The peak disappeared 11 hours after injection. We adapted the time of collection to the C34+ cells mobilization. No CD34+ blood cell rebound was observed after the apheresis was stopped. Our new datas suggest that mobilization of FA patients with G-CSF and plerixafor is safe. However, the age of the patient, a potential cytopenia or the lack of bone marrow progenitor cell may heavely compromise the collection. Nevertheless, the datas show a stable cytopenia despite the stimulation and collection of stem cells during the following months. This study underlines that a very cautious collection of stem cell in the Fanconi anemia to consider gene therapy is a necessity. These results also confirm that the kinetic of CD34+ cells mobilization is one of the key point to a successful stem cell harvesting for gene therapy trial. Disclosures Cavazzana: Smartimmune: Other: Founder of Smartimmune.

New Insights into the Pathophysiology of Acquired Cytopenias

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 18-38 ◽  
Author(s):  
Neal S. Young ◽  
Janis L. Abkowitz ◽  
Lucio Luzzatto
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Cytotoxic T Cell ◽  
Clinical Approach ◽  
Type I ◽  
Red Cell ◽  
Hematopoietic Stem

This review addresses three related bone marrow failure diseases, the study of which has generated important insights in hematopoiesis, red cell biology, and immune-mediated blood cell injury. In Section I, Dr. Young summarizes the current knowledge of acquired aplastic anemia. In most patients, an autoimmune mechanism has been inferred from positive responses to nontransplant therapies and laboratory data. Cytotoxic T cell attack, with production of type I cytokines, leads to hematopoietic stem cell destruction and ultimately pancytopenia; this underlying mechanism is similar to other human disorders of lymphocyte-mediated, tissue-specific organ destruction (diabetes, multiple sclerosis, uveitis, colitis, etc.). The antigen that incites disease is unknown in aplastic anemia as in other autoimmune diseases; post-hepatitis aplasia is an obvious target for virus discovery. Aplastic anemia can be effectively treated by either stem cell transplantation or immunosuppression. Results of recent trials with antilymphocyte globulins and high dose cyclophosphamide are reviewed. Dr. Abkowitz discusses the diagnosis and clinical approach to patients with acquired pure red cell aplasia, both secondary and idiopathic, in Section II. The pathophysiology of various PRCA syndromes including immunologic inhibition of red cell differentiation, viral infection (especially human parvovirus B19), and myelodysplasia are discussed. An animal model of PRCA (secondary to infection with feline leukemia virus [FeLV], subgroup C) is presented. Understanding the mechanisms by which erythropoiesis is impaired provides for insights into the process of normal red cell differentiation, as well as a rational strategy for patient management. Among the acquired cytopenias paroxysmal nocturnal hemoglobinuria (PNH) is relatively rare; however, it can pose formidable management problems. Since its first recognition as a disease, PNH has been correctly classified as a hemolytic anemia; however, the frequent co-existence of other cytopenias has hinted strongly at a more complex pathogenesis. In Section III, Dr. Luzzatto examines recent progress in this area, with special emphasis on the somatic mutations in the PIG-A gene and resulting phenotypes. Animal models of PNH and the association of PNH with bone marrow failure are also reviewed. Expansion of PNH clones must reflect somatic cell selection, probably as part of an autoimmune process. Outstanding issues in treatment are illustrated through clinical cases of PNH. Biologic inferences from PNH may be relevant to our understanding of more common marrow failure syndromes like myelodysplasia.

Erg is required for self-renewal of hematopoietic stem cells during stress hematopoiesis in mice

Blood ◽  
2011 ◽  
Vol 118 (9) ◽  
pp. 2454-2461 ◽  
Author(s):  
Ashley P. Ng ◽  
Stephen J. Loughran ◽  
Donald Metcalf ◽  
Craig D. Hyland ◽  
Carolyn A. de Graaf ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Steady State ◽  
Hematopoietic Stem Cells ◽  
Blood Cells ◽  
Bone Marrow Failure ◽  
Mutant Mice ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Hematopoietic stem cells (HSCs) are rare residents of the bone marrow responsible for the lifelong production of blood cells. Regulation of the balance between HSC self-renewal and differentiation is central to hematopoiesis, allowing precisely regulated generation of mature blood cells at steady state and expanded production at times of rapid need, as well as maintaining ongoing stem cell capacity. Erg, a member of the Ets family of transcription factors, is deregulated in cancers; and although Erg is known to be required for regulation of adult HSCs, its precise role has not been defined. We show here that, although heterozygosity for functional Erg is sufficient for adequate steady-state HSC maintenance, Erg+/Mld2 mutant mice exhibit impaired HSC self-renewal after bone marrow transplantation or during recovery from myelotoxic stress. Moreover, although mice functionally compromised for either Erg or Mpl, the receptor for thrombopoietin, a key regulator of HSC quiescence, maintained sufficient HSC activity to sustain hematopoiesis, Mpl−/−Erg+/Mld2 compound mutant mice displayed exacerbated stem cell deficiencies and bone marrow failure. Thus, Erg is a critical regulator of adult HSCs, essential for maintaining self-renewal at times of high HSC cycling.

New Insights into the Pathophysiology of Acquired Cytopenias

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 18-38 ◽  
Author(s):  
Neal S. Young ◽  
Janis L. Abkowitz ◽  
Lucio Luzzatto
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Cytotoxic T Cell ◽  
Clinical Approach ◽  
Type I ◽  
Red Cell ◽  
Hematopoietic Stem

Abstract This review addresses three related bone marrow failure diseases, the study of which has generated important insights in hematopoiesis, red cell biology, and immune-mediated blood cell injury. In Section I, Dr. Young summarizes the current knowledge of acquired aplastic anemia. In most patients, an autoimmune mechanism has been inferred from positive responses to nontransplant therapies and laboratory data. Cytotoxic T cell attack, with production of type I cytokines, leads to hematopoietic stem cell destruction and ultimately pancytopenia; this underlying mechanism is similar to other human disorders of lymphocyte-mediated, tissue-specific organ destruction (diabetes, multiple sclerosis, uveitis, colitis, etc.). The antigen that incites disease is unknown in aplastic anemia as in other autoimmune diseases; post-hepatitis aplasia is an obvious target for virus discovery. Aplastic anemia can be effectively treated by either stem cell transplantation or immunosuppression. Results of recent trials with antilymphocyte globulins and high dose cyclophosphamide are reviewed. Dr. Abkowitz discusses the diagnosis and clinical approach to patients with acquired pure red cell aplasia, both secondary and idiopathic, in Section II. The pathophysiology of various PRCA syndromes including immunologic inhibition of red cell differentiation, viral infection (especially human parvovirus B19), and myelodysplasia are discussed. An animal model of PRCA (secondary to infection with feline leukemia virus [FeLV], subgroup C) is presented. Understanding the mechanisms by which erythropoiesis is impaired provides for insights into the process of normal red cell differentiation, as well as a rational strategy for patient management. Among the acquired cytopenias paroxysmal nocturnal hemoglobinuria (PNH) is relatively rare; however, it can pose formidable management problems. Since its first recognition as a disease, PNH has been correctly classified as a hemolytic anemia; however, the frequent co-existence of other cytopenias has hinted strongly at a more complex pathogenesis. In Section III, Dr. Luzzatto examines recent progress in this area, with special emphasis on the somatic mutations in the PIG-A gene and resulting phenotypes. Animal models of PNH and the association of PNH with bone marrow failure are also reviewed. Expansion of PNH clones must reflect somatic cell selection, probably as part of an autoimmune process. Outstanding issues in treatment are illustrated through clinical cases of PNH. Biologic inferences from PNH may be relevant to our understanding of more common marrow failure syndromes like myelodysplasia.

scholarly journals Brazilian Consensus Meeting on Pediatric Hematopoietic Stem Cell Transplantation for Acquired Aplastic Anemia and Inherited Bone Marrow Failure Syndromes

JBMTCT ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 151
Author(s):  
Luiz Guilherme Darrigo Junior ◽  
Gisele Loth ◽  
Phillip Scheinberg ◽  
Elias Hallack Atta ◽  
Carmem Bonfim
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Aplastic Anemia ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Bone Marrow Failure ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACQUIRED APLASTIC ANEMIA AND INHERITED BONE MARROW FAILURE SYNDROMES

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