@article{BenischSchillingKleinHitpassetal.2012,
  author    = {Benisch, Peggy and Schilling, Tatjana and Klein-Hitpass, Ludger and Frey, S{\"o}nke P. and Seefried, Lothar and Raaijmakers, Nadja and Krug, Melanie and Regensburger, Martina and Zeck, Sabine and Schinke, Thorsten and Amling, Michael and Ebert, Amling and Jakob, Franz},
  title     = {The Transcriptional Profile of Mesenchymal Stem Cell Populations in Primary Osteoporosis Is Distinct and Shows Overexpression of Osteogenic Inhibitors},
  series = {PLoS One},
  volume    = {7},
  journal   = {PLoS One},
  number    = {9},
  doi       = {10.1371/journal.pone.0045142},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133379},
  pages     = {e45142},
  year      = {2012},
  abstract  = {Primary osteoporosis is an age-related disease characterized by an imbalance in bone homeostasis. While the resorptive aspect of the disease has been studied intensely, less is known about the anabolic part of the syndrome or presumptive deficiencies in bone regeneration. Multipotent mesenchymal stem cells (MSC) are the primary source of osteogenic regeneration. In the present study we aimed to unravel whether MSC biology is directly involved in the pathophysiology of the disease and therefore performed microarray analyses of hMSC of elderly patients (79-94 years old) suffering from osteoporosis (hMSC-OP). In comparison to age-matched controls we detected profound changes in the transcriptome in hMSC-OP, e.g. enhanced mRNA expression of known osteoporosis-associated genes (LRP5, RUNX2, COL1A1) and of genes involved in osteoclastogenesis (CSF1, PTH1R), but most notably of genes coding for inhibitors of WNT and BMP signaling, such as Sclerostin and MAB21L2. These candidate genes indicate intrinsic deficiencies in self-renewal and differentiation potential in osteoporotic stem cells. We also compared both hMSC-OP and non-osteoporotic hMSC-old of elderly donors to hMSC of similar to 30 years younger donors and found that the transcriptional changes acquired between the sixth and the ninth decade of life differed widely between osteoporotic and non-osteoporotic stem cells. In addition, we compared the osteoporotic transcriptome to long term-cultivated, senescent hMSC and detected some signs for pre-senescence in hMSC-OP. Our results suggest that in primary osteoporosis the transcriptomes of hMSC populations show distinct signatures and little overlap with non-osteoporotic aging, although we detected some hints for senescence-associated changes. While there are remarkable inter-individual variations as expected for polygenetic diseases, we could identify many susceptibility genes for osteoporosis known from genetic studies. We also found new candidates, e.g. MAB21L2, a novel repressor of BMP-induced transcription. Such transcriptional changes may reflect epigenetic changes, which are part of a specific osteoporosis-associated aging process.},
  language  = {en}
}
@phdthesis{Schilling2007,
  author    = {Schilling, Tatjana},
  title     = {Transdifferentiation of Human Mesenchymal Stem Cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-24299},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {With ageing, the loss of bone mass correlates with the expansion of adipose tissue in human bone marrow thus facilitating bone-related diseases like osteopenia and osteoporosis. The molecular mechanisms underlying these events are still largely unknown. Reduced osteogenesis and concurrently enhanced adipogenesis might not only occur due to the impairment of conventional osteogenic differentiation originating from mesenchymal stem cells (MSCs). Additionally, transdifferentiation of (pre-)osteoblasts into adipocytes could contribute to the fatty conversion. Therefore, the aim of the present study was to prove the existence of transdifferentiation between the adipogenic and osteogenic lineage and to elucidate molecular mechanisms underlying this phenomenon. At first, a cell culture system of primary human MSCs was established that allowed for differentiation into the adipogenic and osteogenic lineage and proved that the MSC-derived adipocytes and pre-osteoblasts were capable of transdifferentiation (reprogramming) from one into the other lineage. Thereby, lineage-specific markers were completely reversed after reprogramming of pre-osteoblasts into adipocytes. The osteogenic transdifferentiation of adipocytes was slightly less efficient since osteogenic markers were present but the adipogenic ones partly persisted. Hence, plasticity also reached into the differentiation pathways of both lineages and the better performance of adipogenic reprogramming further supported the assumption of its occurrence in vivo. The subsequent examination of gene expression changes by microarray analyses that compared transdifferentiated cells with conventionally differentiated ones revealed high numbers of reproducibly regulated genes shortly after initiation of adipogenic and osteogenic reprogramming. Thereof, many genes were correlated with metabolism, transcription, and signal transduction as FGF, IGF, and Wnt signalling, but only few of the established adipogenesis- and none of the osteogenesis-associated marker genes were detected within 24 h after initiation of transdifferentiation. To find possible key control factors of transdifferentiation amongst the huge amount of regulated genes, a novel bioinformatic scoring scheme was developed that ranked genes due to their potential relevance for reprogramming. Besides the reproducibility and level of their regulation, also the possible reciprocity between the adipogenic and osteogenic transdifferentiation pathway was taken into account. Fibroblast growth factor 1 (FGF1) that ranked as one of the leading candidates to govern reprogramming was proven to inhibit adipogenic differentiation as well as adipogenic transdifferentiation in our cell culture system. Further examination of the FGF signalling pathway and other highly ranked genes could help to better understand the age-related fatty degeneration at the molecular level and therefore provide target molecules for therapeutic modulation of the plasticity of both lineages in order to inhibit adipogenic degeneration and to enhance osteogenesis.},
  subject      = {Zelldifferenzierung},
  language  = {en}
}
@article{TylekBlumHrynevichetal.2020,
  author    = {Tylek, Tina and Blum, Carina and Hrynevich, Andrei and Schlegelmilch, Katrin and Schilling, Tatjana and Dalton, Paul D and Groll, J{\"u}rgen},
  title     = {Precisely defined fiber scaffolds with 40 μm porosity induce elongation driven M2-like polarization of human macrophages},
  series = {Biofabrication},
  volume    = {12},
  journal   = {Biofabrication},
  number    = {2},
  doi       = {10.1088/1758-5090/ab5f4e},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254012},
  year      = {2020},
  abstract  = {Macrophages are key players of the innate immune system that can roughly be divided into the pro-inflammatory M1 type and the anti-inflammatory, pro-healing M2 type. While a transient initial pro-inflammatory state is helpful, a prolonged inflammation deteriorates a proper healing and subsequent regeneration. One promising strategy to drive macrophage polarization by biomaterials is precise control over biomaterial geometry. For regenerative approaches, it is of particular interest to identify geometrical parameters that direct human macrophage polarization. For this purpose, we advanced melt electrowriting (MEW) towards the fabrication of fibrous scaffolds with box-shaped pores and precise inter-fiber spacing from 100 μm down to only 40 μm. These scaffolds facilitate primary human macrophage elongation accompanied by differentiation towards the M2 type, which was most pronounced for the smallest pore size of 40 μm. These new findings can be important in helping to design new biomaterials with an enhanced positive impact on tissue regeneration.},
  language  = {en}
}
@article{BlumTaskinShanetal.2021,
  author    = {Blum, Carina and Taskin, Mehmet Berat and Shan, Junwen and Schilling, Tatjana and Schlegelmilch, Katrin and Teßmar, J{\"o}rg and Groll, J{\"u}rgen},
  title     = {Appreciating the First Line of the Human Innate Immune Defense: A Strategy to Model and Alleviate the Neutrophil Elastase-Mediated Attack toward Bioactivated Biomaterials},
  series = {Small},
  volume    = {17},
  journal   = {Small},
  number    = {13},
  doi       = {10.1002/smll.202007551},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257691},
  year      = {2021},
  abstract  = {Biointerface engineering is a wide-spread strategy to improve the healing process and subsequent tissue integration of biomaterials. Especially the integration of specific peptides is one promising strategy to promote the regenerative capacity of implants and 3D scaffolds. In vivo, these tailored interfaces are, however, first confronted with the innate immune response. Neutrophils are cells with pronounced proteolytic potential and the first recruited immune cells at the implant site; nonetheless, they have so far been underappreciated in the design of biomaterial interfaces. Herein, an in vitro approach is introduced to model and analyze the neutrophil interaction with bioactivated materials at the example of nano-bioinspired electrospun surfaces that reveals the vulnerability of a given biointerface design to the contact with neutrophils. A sacrificial, transient hydrogel coating that demonstrates optimal protection for peptide-modified surfaces and thus alleviates the immediate cleavage by neutrophil elastase is further introduced.},
  language  = {en}
}