Miodrag Stojković

Massachusetts Eye and Ear Infirmary

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Eckhard Wolf

Ludwig-Maximilians-Universität München

Majlinda Lako

Newcastle University

Lyle Armstrong

Newcastle University

Valeri Zakhartchenko

Ludwig-Maximilians-Universität München

Petra Stojković

Massachusetts Eye and Ear Infirmary

Gottfried Brem

University of Veterinary Medicine Vienna

Slaven Erceg

Centro de Investigacion Principe Felipe

Victoria Moreno‐Manzano

Centro de Investigacion Principe Felipe

Vladislav Volarević

University of Kragujevac

Katja Prelle

Bayer (Germany)

Cooperative Institutions

Centro de Investigacion Principe Felipe

Newcastle University

Ludwig-Maximilians-Universität München

Centre for Life

University of Kragujevac

Harvard University

StemCells (United States)

Universitat de València

Technical University of Munich

University College London

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Derivation of Cerebellar Neurons from Human Pluripotent Stem Cells

Current Protocols in Stem Cell Biology (2012)

Slaven Erceg Dunja Lukovic Victoria Moreno‐Manzano Miodrag Stojković Shomi S. Bhattacharya

Here we provide a protocol for differentiation of human embryonic stem cells (hESC) into cerebellar neurons using a novel defined culture method. This protocol is based on the application of inductive signaling factors involved in the early patterning of the cerebellar region of the neural tube, followed by the application of factors responsible for cerebellar neuron specification. Human pluripotent stem cells are induced to form spherical embryonic-like structures called embryoid bodies (EBs) and neuroepithelial tube-like rosettes using defined chemical conditions. In the presence of FGF, Wnt, and RA signaling factors the rosettes were specified to OTX2-expressing cells. Further specification of derived cells involves application of BMP factors involved in early development of granule cell progenitors, followed by mitogens and neurotrophins. It typically takes 5 weeks to generate the functional cerebellar granule neurons. This protocol is feeder-free, applies human recombinant factors, and produces high yield of desired neurons.

Neuroepithelial cell

Embryoid body

10.1002/9780470151808.sc01h05s20

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Citations (30)

Nucleolar proteins and ultrastructure in bovine in vivo developed, in vitro produced, and parthenogenetic cleavage-stage embryos

Molecular Reproduction and Development (2003)

Jozef Laurinčík F. Schmoll Esther Mahabir H Schneider Miodrag Stojković

In the present study, ribosomal RNA (rRNA) gene activation, monitored through nucleolus development, was studied by autoradiography following (3)H-uridine incubation, transmission electron microscopy, and immunofluorescence confocal laser scanning microscopy of key nucleolar proteins involved in rRNA transcription (topoisomerase I, upstream binding factor, and RNA polymerase I) and processing (fibrillarin, nucleolin, and nucleophosmin) in in vivo developed, in vitro produced, and parthenogenetic bovine embryos. In general, in vivo developed embryos displayed formation of fibrillo-granular nucleoli during the 4th post-fertilization cell cycle. During the previous stages of development, nucleolus precursor bodies (NPBs) were observed. However, on some occasions the initial steps of nucleolus formation were observed already at the 2- and 4-cell stage in cases where such embryos were collected from superovulated animals together with later embryonic stages presenting nucleolar development and autoradiographic labeling. The in vitro produced embryos displayed very synchronous formation of fibrillo-granular nucleoli and autoradiographic labeling during the 4th cell cycle. In vivo developed and in vitro produced embryos displayed allocation of nucleolar proteins to fibrillar and granular compartments of the developing nucleoli during the 4th cell cycle. The parthenogenetic embryos typically displayed formation of fibrillo- granular nucleoli during the 5th cell cycle and autoradiographic labeling was not observed until the morula stage. Moreover, the 1-, 2-, and 4-cell parthenogenetic embryos practically lacked NPBs. On the other hand, parthenogenetic embryos displayed allocation of nucleoar proteins to nuclear entities during the 4th cell cycle. In conclusion, both in vivo developed and in vitro produced bovine embryos displayed activation of transcription and nucleolar development during the 4th cell cycle. However, in vivo developed embryos flushed together with later developmental stages displayed premature activation of these processes. Parthenogenetic bovine embryos, on the other hand, displayed a delayed activation.

Parthenogenesis

Cleavage (geology)

Blastomere

10.1002/mrd.10294

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Citations (31)

Downregulation of Multiple Stress Defense Mechanisms During Differentiation of Human Embryonic Stem Cells

Stem Cells (2007)

Gabriele Saretzki Theresia Walter Stuart P. Atkinson João F. Passos Bettina Bareth

Abstract Evolutionary theory predicts that cellular maintenance, stress defense, and DNA repair mechanisms should be most active in germ line cells, including embryonic stem cells that can differentiate into germ line cells, whereas it would be energetically unfavorable to keep these up in mortal somatic cells. We tested this hypothesis by examining telomere maintenance, oxidative stress generation, and genes involved in antioxidant defense and DNA repair during spontaneous differentiation of two human embryonic stem cell lines. Telomerase activity was quickly downregulated during differentiation, probably due to deacetylation of histones H3 and H4 at the hTERT promoter and deacetylation of histone H3 at hTR promoter. Telomere length decreased accordingly. Mitochondrial superoxide production and cellular levels of reactive oxygen species increased as result of increased mitochondrial biogenesis. The expression of major antioxidant genes was downregulated despite this increased oxidative stress. DNA damage levels increased during differentiation, whereas expression of genes involved in different types of DNA repair decreased. These results confirm earlier data obtained during mouse embryonic stem cell differentiation and are in accordance with evolutionary predictions. Disclosure of potential conflicts of interest is found at the end of this article.

10.1634/stemcells.2007-0628

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Citations (254)

CD200 Expression Marks a Population of Quiescent Limbal Epithelial Stem Cells with Holoclone Forming Ability

Stem Cells (2018)

Sanja Bojić Dean Hallam Nuno Alcada Ali E. Ghareeb Rachel Queen

Abstract One of the main challenges in limbal stem cell (LSC) biology and transplantation is the lack of definitive cell surface markers which can be used to identify and enrich viable LSCs. In this study, expression of 361 cell surface proteins was assessed in ex vivo expanded limbal epithelial cells. One marker, CD200 was selected for further characterization based on expression in a small subset of limbal epithelial cells (2.25% ± 0.69%) and reduced expression through consecutive passaging and calcium induced differentiation. CD200 was localized to a small population of cells at the basal layer of the human and mouse limbal epithelium. CD200+cells were slow cycling and contained the majority of side population (SP) and all the holoclone forming progenitors. CD200+ cells displayed higher expression of LSCs markers including PAX6, WNT7A, CDH3, CK14, CK15, and ABCB5 and lower expression of Ki67 when compared to CD200−. Downregulation of CD200 abrogated the ability of limbal epithelial cells to form holoclones, suggesting an important function for CD200 in the maintenance and/or self-renewal of LSCs. A second marker, CD109, which was expressed in 56.29% ± 13.96% of limbal epithelial cells, was also found to co-localize with ΔNp63 in both human and mouse cornea, albeit more abundantly than CD200. CD109 expression decreased slowly through calcium induced cell differentiation and CD109+ cells were characterized by higher expression of Ki67, when compared to CD109− subpopulation. Together our data suggest that CD200 expression marks a quiescent population of LSCs with holoclone forming potential, while CD109 expression is associated with a proliferative progenitor phenotype.

Limbal stem cell

Stem cell marker

PAX6

Ex vivo

10.1002/stem.2903

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Citations (23)

Locomotor Recovery After Spinal Cord Transection: Transplantation of Oligodendrocytes and Motoneuron Progenitors Generated from Human Embryonic Stem Cells

Springer eBooks (2012)

Slaven Erceg Miodrag Stojković

Remyelination

10.1007/978-94-007-2866-0_24

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Citations (0)

Stem Cells Appoints Four Associate Editors

Stem Cells (2008)

Donald G. Phinney Miodrag Stojković

10.1634/stemcells.2008-0340

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Trichostatin A affects histone acetylation and gene expression in porcine somatic cell nucleus transfer embryos

Theriogenology (2009)

R.P. Cervera Nuria Martí‐Gutiérrez E. Escorihuela Rubén Moreno Miodrag Stojković

Trichostatin A

Genomic Imprinting

Histone H4

Homeobox protein NANOG

Inner cell mass

Reprogramming

10.1016/j.theriogenology.2009.06.030

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Citations (83)

Mesenchymal Stem Cells: A Friend or Foe in Immune-Mediated Diseases

Stem Cell Reviews and Reports (2015)

Marina Gazdic Vladislav Volarević Nebojša Arsenijević Miodrag Stojković

10.1007/s12015-014-9583-3

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Citations (216)

Concise Review: Reactive Astrocytes and Stem Cells in Spinal Cord Injury: Good Guys or Bad Guys?

Stem Cells (2015)

Dunja Lukovic Miodrag Stojković Victoria Moreno‐Manzano Pavla Jendelová Eva Syková

Spinal cord injury (SCI) usually results in long lasting locomotor and sensory neuron degeneration below the injury. Astrocytes normally play a decisive role in mechanical and metabolic support of neurons, but in the spinal cord they cause injury, exerting well-known detrimental effects that contribute to glial scar formation and inhibition of axon outgrowth. Cell transplantation is considered a promising approach for replacing damaged cells and promoting neuroprotective and neuroregenerative repair, but the effects of the grafted cells on local tissue and the regenerative properties of endogenous neural stem cells in the injured spinal cord are largely unknown. During the last 2 decades cumulative evidence from diverse animal models has indicated that reactive astrocytes in synergy with transplanted cells could be beneficial for injury in multiple ways, including neuroprotection and axonal growth. In this review, we specifically focus on the dual opposing roles of reactive astrocytes in SCI and how they contribute to the creation of a permissive environment when combined with transplanted cells as the influential components for a local regenerative niche. Modulation of reactive astrocyte function might represent an extremely attractive new therapy to enhance the functional outcomes in patients.

10.1002/stem.1959

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Citations (113)

Intracytoplasmic sperm injection in bovine: Effects of oocyte activation, sperm pretreatment and injection technique

Theriogenology (2000)

R. Suttner Valeri Zakhartchenko Petra Stojković Sigrid Müller Ramiro Alberio

Oocyte activation

10.1016/s0093-691x(00)00403-9

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Citations (91)