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stem cell expansion

Annette Künkele, Christopher Brown, Adam Beebe, Stephanie Mgebroff, Adam J Johnson, Agne Taraseviciute, Lisa S Rolczynski, Cindy A Chang, Olivia C Finney, Julie R Park, Michael C Jensen
Cytotoxic chemotherapy and radiation can render lymphocyte repertoires qualitatively and quantitatively defective. Thus, heavily treated patients are often poor candidates for the manufacture of autologous CAR-T cell products. In the USA and Europe, children with high-risk neuroblastoma undergo apheresis early in the course of their treatment to collect peripheral blood stem cells (PBSCs) for cryopreservation in preparation for high-dose chemotherapy followed by autologous stem cell rescue. Here, we investigate whether these cryopreserved chemotherapy and G-CSF-mobilized PBSCs can be utilized as starting material for CAR-T cell manufacturing...
October 10, 2018: Biology of Blood and Marrow Transplantation
Edward Ayoub, Michael P Wilson, Kathleen E McGrath, Allison J Li, Benjamin J Frisch, James Palis, Laura M Calvi, Yi Zhang, Archibald S Perkins
Inv(3q26) and t(3:3)(q21;q26) are specific to poor-prognosis myeloid malignancies, and result in marked overexpression of EVI1, a zinc-finger transcription factor and myeloid-specific oncoprotein. Despite extensive study, the mechanism by which EVI1 contributes to myeloid malignancy remains unclear. Here we describe a new mouse model that mimics the transcriptional effects of 3q26 rearrangement. We show that EVI1 overexpression causes global distortion of hematopoiesis, with suppression of erythropoiesis and lymphopoiesis, and marked premalignant expansion of myelopoiesis that eventually results in leukemic transformation...
October 12, 2018: Nature Communications
Rui Wang, Chenguang Zhao, Jianjun Li, Yuhuan Li, Ying Liu, Hui Dong, Dong Wang, Bo Zhao, Xin Zhang, Shuang Wang, Feng Cui, Haopeng Li, Xijing He, Jie Qin
Neural stem and progenitor cells (NSPCs) are important for nerve regeneration after spinal cord injury (SCI). Their proliferation, however, is limited. In this study, we investigated the role of Notch1 signaling in NSPC proliferation using adult mouse spinal cord derived NSPCs. We observed that Notch1 promoted proliferation of NSPCs and that Notch1 overexpression led to an expansion of cells in the S-phase and increased cyclin D1 expression. When investigating the functional relationship between Notch1, p-p38 and Pax6, we found that Notch1 suppressed p-p38 while promoting Pax6 expression...
October 9, 2018: Experimental Cell Research
Chenchun Wu, Shuran Yu, Qianxia Tan, Peng Guo, Huining Liu
Choriocarcinoma is sensitive to chemotherapy. However, drug resistance has become one of the major problems in recent years. Previous studies have shown that many tumors contained a small fraction of cells that exhibited enhanced tumor initiating potential and stem cell-like properties. It is hypothesized that cancer stem cells (CSCs) are organized in a cellular hierarchy. They also have the qualities of self-renewal, chemoresistance, and so on. The identification of CSCs in choriocarcinoma and the mechanism contributing to their qualities remain largely unknown...
October 12, 2018: Cell Cycle
Constanza E Martínez, Roberto Gómez, Alexis M Kalergis, Patricio C Smith
OBJECTIVES: Cell-based therapies involve the need to expand cell cultures ex vivo for their subsequent implantation in an autologous manner. An important limitation regarding this technology is the use of fetal bovine serum (FBS) that has critical safety limitations. Platelet-derived fractions represent an autologous source of growth factors that may be used for the expansion of these cell cultures. Periodontal ligament (PDL) cells comprise a heterogeneous cell population that may not necessarily respond in a uniform manner to proliferative stimuli...
October 11, 2018: Clinical Oral Investigations
Keiichiro Kamura, Jihoon Shin, Hiroshi Kiyonari, Takaya Abe, Go Shioi, Atsunori Fukuhara, Hiroshi Sasaki
Obesity is characterized by an expansion of white adipose tissue (WAT) mass, which mainly consists of adipocytes. During the commitment and differentiation of adipocytes, PPARγ functions as a key transcriptional factor for adipogenesis, and is associated with its suppressive coregulator, TAZ. Previous studies have shown the importance of TAZ in adipogenesis using an in vitro model; however, the understanding of its role in adipogenesis in vivo remains limited. Here, we report a unique obese mouse model that is associated with TAZ downregulation, which arose from the overexpression of Yap, a Taz paralog...
October 9, 2018: Biochemical and Biophysical Research Communications
Raheleh Farahzadi, Ezzatollah Fathi, Seyed Alireza Mesbah-Namin, Nosratollah Zarghami
The identification of factors that reduce the senescent tendency of the mesenchymal stem cells (MSCs) upon expansion has great potential for cellular therapies in regenerative medicine. Previous studies have shown the aging protective effect of L-carnitine (LC). On the other hand, reduction in proliferation potential and age-dependent decline in number and functions of MSCs were accompanied by telomere shortening, reduction in telomerase activity and epigenetic changes. The aim of this study was to evaluate the effects of LC on aging of MSCs through telomerase activity assessment and the investigation of methylation status of the hTERT gene promoter...
October 2018: Tissue & Cell
Ben Antebi, Luis A Rodriguez, Kerfoot P Walker, Amber M Asher, Robin M Kamucheka, Lucero Alvarado, Arezoo Mohammadipoor, Leopoldo C Cancio
BACKGROUND: In the bone marrow, MSCs reside in a hypoxic milieu (1-5% O2 ) that is thought to preserve their multipotent state. Typically, in vitro expansion of MSCs is performed under normoxia (~ 21% O2 ), a process that has been shown to impair their function. Here, we evaluated the characteristics and function of MSCs cultured under hypoxia and hypothesized that, when compared to normoxia, dedicated hypoxia will augment the functional characteristics of MSCs. METHODS: Human and porcine bone marrow MSCs were obtained from fresh mononuclear cells...
October 11, 2018: Stem Cell Research & Therapy
A R Caseiro, G Ivanova, S S Pedrosa, M V Branquinho, P Georgieva, P P Barbosa, J D Santos, R Magalhães, P Teixeira, T Pereira, A C Maurício
Mesenchymal Stromal cells (MSCs) have a potential role in cell-based therapies. Foetal bovine serum (FBS) is used to supplement the basal cell culture medium but presents several disadvantages and risks. Other alternatives have been studied, including human umbilical cord blood plasma (hUCBP), aiming at the development of xeno-free culturing protocols. A comparative characterization of multicomponent metabolic composition of hUCBP and commercial FBS based on Nuclear Magnetic Resonance (NMR) spectroscopy and multivariate statistical analysis was performed...
2018: PloS One
Tiffany Leidy-Davis, Kai Cheng, Leslie O Goodwin, Judith L Morgan, Wen Chun Juan, Xavier Roca, S Tiong Ong, David E Bergstrom
Here, we describe an expansion of the typical DNA size limitations associated with CRISPR knock-in technology, more specifically, the physical extent to which mouse genomic DNA can be replaced with donor (in this case, human) DNA at an orthologous locus by zygotic injection. Driving our efforts was the desire to create a whole animal model that would replace 17 kilobase pairs (kbp) of the mouse Bcl2l11 gene with the corresponding 25-kbp segment of human BCL2L11, including a conditionally removable segment (2...
October 9, 2018: Scientific Reports
Stéphane Terry, Rania Faouzi Zaarour, Goutham Hassan Venkatesh, Amirtharaj Francis, Walid El-Sayed, Stéphanie Buart, Pamela Bravo, Jérome Thiery, Salem Chouaib
Hypoxia, or gradients of hypoxia, occurs in most growing solid tumors and may result in pleotropic effects contributing significantly to tumor aggressiveness and therapy resistance. Indeed, the generated hypoxic stress has a strong impact on tumor cell biology. For example, it may contribute to increasing tumor heterogeneity, help cells gain new functional properties and/or select certain cell subpopulations, facilitating the emergence of therapeutic resistant cancer clones, including cancer stem cells coincident with tumor relapse and progression...
October 6, 2018: International Journal of Molecular Sciences
Pamela Y Ting, Albert E Parker, J Scott Lee, Chris Trussell, Orzala Sharif, Fabio Luna, Glenn Federe, S Whitney Barnes, John R Walker, Julie Vance, Mu-Yun Gao, Heath E Klock, Scott Clarkson, Carsten Russ, Loren J Miraglia, Michael P Cooke, Anthony E Boitano, Peter McNamara, John Lamb, Christian Schmedt, Jennifer L Snead
CRISPR-Cas9 screening allows genome-wide interrogation of gene function. Currently, to achieve the high and uniform Cas9 expression desirable for screening, one needs to engineer stable and clonal Cas9-expressing cells-an approach that is not applicable in human primary cells. Guide Swap permits genome-scale pooled CRISPR-Cas9 screening in human primary cells by exploiting the unexpected finding that editing by lentivirally delivered, targeted guide RNAs (gRNAs) occurs efficiently when Cas9 is introduced in complex with nontargeting gRNA...
October 8, 2018: Nature Methods
Evans K Afenya, Rachid Ouifki, Suneel D Mundle
The cancer stem cell hypothesis has gained currency in recent times but concerns remain about its scientific foundations because of significant gaps that exist between research findings and comprehensive knowledge about cancer stem cells (CSCs). In this light, a mathematical model that considers hematopoietic dynamics in the diseased state of the bone marrow and peripheral blood is proposed and used to address findings about CSCs. The ensuing model, resulting from a modification and refinement of a recent model, develops out of the position that mathematical models of CSC development, that are few at this time, are needed to provide insightful underpinnings for biomedical findings about CSCs as the CSC idea gains traction...
October 5, 2018: Journal of Theoretical Biology
Rosa Pennisi, Jacopo Albanesi, Paolo Ascenzi, Clara Nervi, Alessandra di Masi
Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the expansion of hematopoietic stem/progenitor cells (HPCs) blocked at different stages of maturation/differentiation. The poor outcome of AMLs necessitates therapeutic improvement. In AML, genes encoding for myeloid transcription factors, signaling receptors regulating cell proliferation, and epigenetic modifiers can be mutated by somatically acquired genetic mutations or altered by chromosomal translocations. These mutations modify chromatin organization at genes sites regulating HPCs proliferation, terminal differentiation, and DNA repair, contributing to the development and progression of the disease...
October 8, 2018: IUBMB Life
Keykavos Gholami, Gholamreza Pourmand, Morteza Koruji, Mohammadali Sadighigilani, Shadan Navid, Fariborz Izadyar, Mehdi Abbasi
Optimization of in vitro culture system for the expansion and the maturation of male germ cells to post meiotic stages is a valuable tool for studies exploring spermatogenesis regulation and the management of male infertility. Several studies have reported promising results of mouse spermatogonial stem cells culture in three-dimensional (3D) culture systems and a subsequent production of sperm. In the present study, we investigated the capacity of a three-dimensional soft agar culture system (SACS) supplemented with Knockout Serum Replacement (KSR) in colony formation and inducing human germ cells to reach post-meiotic stages...
October 2, 2018: Reproductive Biology
Sapana Jalnapurkar, Ranjita Devi Moirangthem, Shweta Singh, Lalita Limaye, Vaijayanti Kale
Patients with leukemia, lymphoma, severe aplastic anemia, etc. are frequently the targets of bone marrow transplantation, the success of which critically depends on efficient engraftment by transplanted hematopoietic cells (HSCs). Ex vivo manipulation of HSCs to improve their engraftment ability becomes necessary when the number or quality of donor HSCs is a limiting factor. Due to their hematopoiesis-supportive ability, bone marrow-derived mesenchymal stromal cells (MSCs) have been traditionally used as feeder layers for ex vivo expansion of HSCs...
October 5, 2018: Stem Cells
Charlotte M Mousset, Willemijn Hobo, Yun Ji, Hanny Fredrix, Valeria De Giorgi, Robert D Allison, Michel G D Kester, J H Frederik Falkenburg, Nicolaas P M Schaap, Joop H Jansen, Luca Gattinoni, Harry Dolstra, Anniek B van der Waart
Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action...
2018: Oncoimmunology
Natalie A Twine, Linda Harkness, James Adjaye, Abdullah Aldahmash, Marc R Wilkins, Moustapha Kassem
Long-term in vitro expansion of bone marrow stromal (skeletal) stem cells (also known as human mesenchymal stem cells [hMSC]) is associated with replicative senescence and impaired functions. We have previously reported that telomerization of hMSC through hTERT overexpression led to bypassing a replicative senescence phenotype and improved in vitro and in vivo functions. However, the molecular consequence of telomerization is poorly characterized. Thus, we compared the molecular phenotype of a well-studied telomerized hMSC (hMSC-TERT) cell line with primary hMSC...
September 2018: JBMR Plus
Yanpeng Yuan, Xihe Tang, Yun-Fei Bai, Shuyan Wang, Jing An, Yanchuan Wu, Zhi-Qing David Xu, Y Alex Zhang, Zhiguo Chen
Autologous neural stem cells (NSCs) may offer a promising source for deriving dopaminergic (DA) cells for treatment of Parkinson's disease (PD). Methods: By using Sendai virus, human peripheral blood mononuclear cells (PBMNCs) were reprogrammed to induced NSCs (iNSCs), which were then differentiated to dopaminergic neurons in vitro . Whole-genome deep sequencing was performed to search for mutations that had accumulated during the reprogramming and expansion processes. To find the optimal differentiation stage of cells for transplantation, DA precursors obtained at various differentiation time points were tested by engraftment into brains of naïve immunodeficient mice...
2018: Theranostics
Xiaojiao Li, Xiaodong Xie, Zhiwei Ma, Qian Li, Lin Liu, Xingjie Hu, Chang Liu, Bin Li, Hui Wang, Nan Chen, Chunhai Fan, Haiyun Song
Stem cells generally exist in low abundance and tend to lose stemness in the absence of self-renewal signals. While extracellular-matrix-mimicking techniques have been developed to support stem cell proliferation, the lack of niche cells in these synthetic systems often hampers continuous stem cell expansion and maintenance of pluripotency, which are indispensable for regenerative medicine. Here, an intercellular DNA-reaction-programmed ESPN (expansion of stem cells with pairing niches) strategy is developed for 3D culture of mammary stem cells (MaSCs)...
October 1, 2018: Advanced Materials
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