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      Evaluation of hematopoietic stem cell expansion in the presence of garcinol

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          Abstract

          Objective:

          The application of human cord blood (hCB) is limited to children by using relatively small volume of cord blood that does not contain enough hematopoietic stem cells (HSCs). So, efforts for applying cord blood stem cells in transplantation have led to establishment of some approaches for ex vivo expansion of HSCs such as garcinol.

          Materials and Methods:

          CD133+ HSCs were separated by a magnetic-activated cell sorting (MACS) system. Isolated cells were cultured with different doses of garcinol, SCF, TPO and FLT-3L. The optimal dose of garcinol for ex vivo expansion of HSCs was determined by direct counting. Flow cytometry was used to evaluate the expression of CD133 marker to check the ability of garcinol in maintenance of HSCs. Colony forming cell (CFC) assay was performed to evaluate clonogenic capability of treated cells. The level of expression of CXCR4 gene was evaluated by RT-PCR. Data were analyzed using Student’s t test.

          Results:

          Our results showed that CD133 + HSCs in the presence of garcinol (5-10 µM) had high expansion activity and cell counting showed that the number of cells in treated group was higher than control group (1.9 –fold) and CFC assay showed that the number of colonies following treatment with garcinol had 1.3-fold increase. Treatment of HSCs with garcinol resulted in 9.6-fold increase in terms of CXCR4 expression in comparison to control group.

          Conclusion:

          The present study showed that garcinol can improve ex vivo expansion of HSCs and enhance their potential for homing to bone marrow.

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          Most cited references29

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          Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.

          Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy.
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            Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells.

            The purpose of this study was to evaluate human umbilical cord blood as an alternative to bone marrow in the provision of transplantable stem/progenitor cells for hematopoietic reconstitution. Although no direct quantitative assay for human hematopoietic repopulating cells is at present available, the granulocyte-macrophage progenitor cell (CFU-GM) assay has been used with success as a valid indicator of engrafting capability. We examined greater than 100 collections of human umbilical cord blood for their content of nucleated cells and granulocyte-macrophage, erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells, in many cases both before and after cryopreservation. First it was determined that granulocyte-macrophage, erythroid, and multipotential progenitor cells remained functionally viable in cord blood untreated except for addition of anticoagulant for at least 3 days at 4 degrees C or 25 degrees C (room temperature), though not at 37 degrees C, implying that these cells could be satisfactorily studied and used or cryopreserved for therapy after transport of cord blood by overnight air freight carriage from a remote obstetrical service. Granulocyte-macrophage progenitor cells from cord blood so received responded normally to stimulation by purified recombinant preparations of granulocyte-macrophage, granulocyte, and macrophage colony-stimulating factors and interleukin 3. The salient finding, based on analysis of 101 cord blood collections, is that the numbers of progenitor cells present in the low-density (less than 1.077 gm/ml) fraction after Ficoll/Hypaque separation typically fell within the range that has been reported for successful engraftment by bone marrow cells. Another observation of practical importance is that procedures to remove erythrocytes or granulocytes prior to freezing, and washing of thawed cells before plating, entailed large losses of progenitor cells, the yield of unwashed progenitor cells from unfractionated cord blood being many times greater. The provisional inference is that human umbilical cord blood from a single individual is typically a sufficient source of cells for autologous (syngeneic) and for major histocompatibility complex-matched allogeneic hematopoietic reconstitution.
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              Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1.

              The Polycomb group (PcG) gene Bmi-1 has recently been implicated in the maintenance of hematopoietic stem cells (HSC) from loss-of-function analysis. Here, we demonstrate that increased expression of Bmi-1 promotes HSC self-renewal. Forced expression of Bmi-1 enhanced symmetrical cell division of HSCs and mediated a higher probability of inheritance of stemness through cell division. Correspondingly, forced expression of Bmi-1, but not the other PcG genes, led to a striking ex vivo expansion of multipotential progenitors and marked augmentation of HSC repopulating capacity in vivo. Loss-of-function analyses revealed that among PcG genes, absence of Bmi-1 is preferentially linked with a profound defect in HSC self-renewal. Our findings define Bmi-1 as a central player in HSC self-renewal and demonstrate that Bmi-1 is a target for therapeutic manipulation of HSCs.
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                Author and article information

                Journal
                Avicenna J Phytomed
                Avicenna J Phytomed
                IJP
                Avicenna Journal of Phytomedicine
                Mashhad University of Medical Sciences (Mashhad, Iran )
                2228-7930
                2228-7949
                Jul-Aug 2018
                : 8
                : 4
                : 350-357
                Affiliations
                [1 ] Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
                [2 ] Stem Cell and Tissue Engineering Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
                [3 ] Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                Author notes
                [* ]Corresponding Author: Tel: +982182884508, Fax: +982188013030, soleim_m@modares.ac.ir
                Article
                AJP-8-350
                6204147
                2a167c53-04c4-4c0d-867a-28047bc03726

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 September 2016
                : 2 November 2017
                : 19 December 2017
                Categories
                Original Research Article

                hematopoietic stem cells,expansion,garcinol,small-molecule compounds

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