Pitfalls and fallacies interfering with correct identification of embryonic stem cells implanted into the brain after experimental traumatic injury

Molcanyi, Marek; Bosche, Bert; Kraitsy, Klaus; Patz, Silke; Živčák, Jozef; Rieß, Peter; Majdoub, Faycal El; Hescheler, Jürgen; Goldbrunner, Roland; Schäfer, Ute

doi:10.1016/j.jneumeth.2013.02.012

Cited by 17 publications

(19 citation statements)

References 68 publications

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“…Several groups have reported strong recruitment of macrophages after transplantation of ESC or ESC derivatives undergoing active rejection [19, 20]. Sionov et al observed that adult macrophages could destroy the inner cell mass (which contain ESCs) from early blastocysts but that the trophoblast repelled these macrophages, suggesting a possible biological mechanism to protect the inner cell mass cells from the maternal (host) immune system macrophages during early embryonic development [18].…”

Section: Discussionmentioning

confidence: 99%

F4/80⁺Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor EngraftmentIn Vivo

Thompson

Rooijen

McLelland

et al. 2016

Journal of Immunology Research

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Understanding how embryonic stem cells and their derivatives interact with the adult host immune system is critical to developing their therapeutic potential. Murine embryonic stem cell-derived hematopoietic progenitors (ESHPs) were generated via coculture with the bone marrow stromal cell line, OP9, and then transplanted into NOD.SCID.Common Gamma Chain (NSG) knockout mice, which lack B, T, and natural killer cells. Compared to control mice transplanted with adult lineage-negative bone marrow (Lin− BM) progenitors, ESHP-transplanted mice attained a low but significant level of donor hematopoietic chimerism. Based on our previous studies, we hypothesized that macrophages might contribute to the low engraftment of ESHPs in vivo. Enlarged spleens were observed in ESHP-transplanted mice and found to contain higher numbers of host F4/80+ macrophages compared to BM-transplanted controls. In vivo depletion of host macrophages using clodronate-loaded liposomes improved the ESHP-derived hematopoietic chimerism in the spleen but not in the BM. F4/80+ macrophages demonstrated a striking propensity to phagocytose ESHP targets in vitro. Taken together, these results suggest that macrophages are a barrier to both syngeneic and allogeneic ESHP engraftment in vivo.

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Section: Discussionmentioning

confidence: 99%

F4/80⁺Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor EngraftmentIn Vivo

Thompson

Rooijen

McLelland

et al. 2016

Journal of Immunology Research

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“…Previously, the cellular immune response was shown to be responsible for scavenging the stem cell grafts implanted into the central nervous system (Li et al, 2005; Molcanyi et al, 2007). Immune system activation has been observed and attributed to different mechanisms, such as rejection, the removal of necrotic and/or apoptotic cells, or the combination of trauma and transplantation stimulus (Olanow et al, 2003; Li et al, 2005; Molcanyi et al, 2007, 2013; Pereira et al, 2011). Immune cell infiltration observed in the current study was very likely due to macrophage activation (first line defense) as a response to a local stimulus (needle injury and grafting of heterotopic cell suspension), rather than a specific host-versus-graft rejection.…”

Section: Discussionmentioning

confidence: 99%

“…ESC migration and differentiation was reported in ischemic animals (Hoehn et al, 2002; Erdo et al, 2003). In contrast, neurological improvement followed by gradual loss of implanted cells, came to the forefront in TBI-injured rats receiving ESC grafts (Molcanyi et al, 2007, 2013; Riess et al, 2007). Nestin was, inter alia , utilized to examine early differentiation along the neural pathway in injured animals.…”

Section: Introductionmentioning

confidence: 99%

“…However, nestin staining was abundant at trauma and implantation sites and was predominantly expressed by cells lacking any co-localization with GFP (e.g., activated resident glia). Additional presence of nestin-expressing, GFP-negative spindle-shaped cellular elements localized inside the implanted graft was observed during confocal analysis of the implanted grafts; however, it was not systematically evaluated in our previous studies (see Supplementary Material) (Molcanyi et al, 2007, 2013). Current re-assessment of previous observations (Molcanyi et al, 2007, 2009) revealed the presence of such cells in several grafted animals.…”

Section: Introductionmentioning

confidence: 99%

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Impurity of Stem Cell Graft by Murine Embryonic Fibroblasts â€“ Implications for Cell-Based Therapy of the Central Nervous System

Molcanyi

Mehrjardi

Schäfer

et al. 2014

Front. Cell. Neurosci.

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Stem cells have been demonstrated to possess a therapeutic potential in experimental models of various central nervous system disorders, including stroke. The types of implanted cells appear to play a crucial role. Previously, groups of the stem cell network NRW implemented a feeder-based cell line within the scope of their projects, examining the implantation of stem cells after ischemic stroke and traumatic brain injury. Retrospective evaluation indicated the presence of spindle-shaped cells in several grafts implanted in injured animals, which indicated potential contamination by co-cultured feeder cells (murine embryonic fibroblasts – MEFs). Because feeder-based cell lines have been previously exposed to a justified criticism with regard to contamination by animal glycans, we aimed to evaluate the effects of stem cell/MEF co-transplantation. MEFs accounted for 5.3 ± 2.8% of all cells in the primary FACS-evaluated co-culture. Depending on the culture conditions and subsequent purification procedure, the MEF-fraction ranged from 0.9 to 9.9% of the cell suspensions in vitro. MEF survival and related formation of extracellular substances in vivo were observed after implantation into the uninjured rat brain. Impurity of the stem cell graft by MEFs interferes with translational strategies, which represents a threat to the potential recipient and may affect the graft microenvironment. The implications of these findings are critically discussed.

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“…Additionally, the efficacy of such treatments at present does not yet match the long-term promise 90, 91 . Despite this, there is potential for good.…”

Section: Possible New Directions For Researchmentioning

confidence: 99%

New innovations: Therapeutic opportunities for intellectual disabilities

Picker

Walsh

2013

Annals of Neurology

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Intellectual disability is common and is associated with significant morbidity. Until the latter half of the twentieth century there were no efficacious treatments. Following initial breakthroughs associated with newborn screening and metabolic corrections, little progress was made until recently. With improved understanding of genetic and cellular mechanisms, novel treatment options are beginning to appear for a number of specific conditions. Fragile X and Tuberous sclerosis offer paradigms for the development of targeted therapeutics but advances in understanding of other disorders such as Down syndrome and Rett syndrome for example are also resulting in promising treatment directions. In addition, better understanding of the underlying neurobiology is leading to novel developments in enzyme replacement for storage disorders, adjunctive therapies for metabolic disorders; as well as potentially more generalizable approaches that target dysfunctional cell regulation via RNA and chromatin. Physiologic therapies, including deep brain stimulation and transcranial magnetic stimulation, offer yet another direction to enhance cognitive functioning. Current options and evolving opportunities for the intellectually disabled are reviewed and exemplified. Global significance of intellectual disability

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Pitfalls and fallacies interfering with correct identification of embryonic stem cells implanted into the brain after experimental traumatic injury

Cited by 17 publications

References 68 publications

F4/80⁺Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor EngraftmentIn Vivo

F4/80⁺Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor EngraftmentIn Vivo

Impurity of Stem Cell Graft by Murine Embryonic Fibroblasts â€“ Implications for Cell-Based Therapy of the Central Nervous System

New innovations: Therapeutic opportunities for intellectual disabilities

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Pitfalls and fallacies interfering with correct identification of embryonic stem cells implanted into the brain after experimental traumatic injury

Cited by 17 publications

References 68 publications

F4/80+Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor EngraftmentIn Vivo

F4/80+Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor EngraftmentIn Vivo

Impurity of Stem Cell Graft by Murine Embryonic Fibroblasts â€“ Implications for Cell-Based Therapy of the Central Nervous System

New innovations: Therapeutic opportunities for intellectual disabilities

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Product

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F4/80⁺Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor EngraftmentIn Vivo

F4/80⁺Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor EngraftmentIn Vivo