1. |
-
- 2019
-
Journal article (peer-reviewed)
|
|
2. |
- Huttner, Hagen B., et al.
(author)
-
Meningioma growth dynamics assessed by radiocarbon retrospective birth dating
- 2018
-
In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 27, s. 176-181
-
Journal article (peer-reviewed)abstract
- It is not known how long it takes from the initial neoplastic transformation of a cell to the detection of a tumor, which would be valuable for understanding tumor growth dynamics. Meningiomas show a broad histological, genetic and clinical spectrum, are usually benign and considered slowly growing. There is an intense debate regarding their age and growth pattern and when meningiomas should be resected. We have assessed the age and growth dynamics of 14 patients with meningiomas (WHO grade I: n = 6 with meningothelial and n = 6 with fibrous subtype, as well as n = 2 atypical WHO grade II meningiomas) by combining retrospective birth-dating of cells by analyzing incorporation of nuclear-bomb-test-derived 14C, analysis of cell proliferation, cell density, MRI imaging and mathematical modeling. We provide an integrated model of the growth dynamics of benign meningiomas. The mean age of WHO grade I meningiomas was 22.1 ± 6.5 years, whereas atypical WHO grade II meningiomas originated 1.5 ± 0.1 years prior to surgery (p < 0.01). We conclude that WHO grade I meningiomas are very slowly growing brain tumors, which are resected in average two decades after time of origination.
|
|
3. |
- Roeder, Sebastian S., et al.
(author)
-
Tracking cell turnover in human brain using 15N-thymidine imaging mass spectrometry
- 2023
-
In: Frontiers in Neuroscience. - 1662-4548. ; 17
-
Journal article (peer-reviewed)abstract
- Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly.
|
|
4. |
- Dias, David O., et al.
(author)
-
Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
- 2021
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
-
Journal article (peer-reviewed)abstract
- Fibrotic scar tissue limits central nervous system regeneration in adult mammals. The extent of fibrotic tissue generation and distribution of stromal cells across different lesions in the brain and spinal cord has not been systematically investigated in mice and humans. Furthermore, it is unknown whether scar-forming stromal cells have the same origin throughout the central nervous system and in different types of lesions. In the current study, we compared fibrotic scarring in human pathological tissue and corresponding mouse models of penetrating and non-penetrating spinal cord injury, traumatic brain injury, ischemic stroke, multiple sclerosis and glioblastoma. We show that the extent and distribution of stromal cells are specific to the type of lesion and, in most cases, similar between mice and humans. Employing in vivo lineage tracing, we report that in all mouse models that develop fibrotic tissue, the primary source of scar-forming fibroblasts is a discrete subset of perivascular cells, termed type A pericytes. Perivascular cells with a type A pericyte marker profile also exist in the human brain and spinal cord. We uncover type A pericyte-derived fibrosis as a conserved mechanism that may be explored as a therapeutic target to improve recovery after central nervous system lesions.
|
|
5. |
- Huttner, Hagen B
(author)
-
Investigating cell turnover in the healthy and diseased adult human brain
- 2016
-
Doctoral thesis (other academic/artistic)abstract
- For decades it was thought that cells that lost in the human central nervous system because of ageing or disease – different from other cell tissues – cannot be replaced and that in humans all neurons are generated during prenatal development. However, over the last 20 years, it became obvious that there is a certain level of adult neurogenesis in most mammals that mainly occurs in the dentate gyrus and the subventricular zone. Whether or not findings from animal studies also hold true in humans was difficult to study as direct evidence – as obtained in animals from genomic labeling using for instance nucleosides like BrdU – was not feasible in humans because of ethical considerations. The establishment of the so-called radiocarbon technique, a method taking advantage of the above-ground nuclear bomb tests during the Cold War to retrospectively birth date cells by determination of the 12C/14C ratio in genomic DNA – allowed to investigate the age and the turnover dynamics of cells in various human tissues. Applying this technique we here (i) studied whether there is adult neurogenesis in the healthy human brain, specifically within the hippocampus, (ii) studied whether there is adult neurogenesis in the diseased human brain, specifically in response to cortical stroke, and (iii) investigated the age and growth dynamics of brain tumors, specifically benign meningiomas. In essence we demonstrate (i) that there is a lifelong adult neurogenesis within the human hippocampus and provide an integrated model of hippocampal cell turnover dynamics, (ii) that there is no significant induction of cortical neurogenesis following ischemic cortical stroke in humans, and (iii) that the age of benign meningiomas is significantly older than that of more malignant brain tumors. The clinical implications of these findings are discussed and research projects for future studies identified.
|
|
6. |
- Huttner, Hagen B, et al.
(author)
-
The age and genomic integrity of neurons after cortical stroke in humans
- 2014
-
In: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 17:6, s. 801-803
-
Journal article (peer-reviewed)abstract
- It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test-derived (14)C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.
|
|