Publications by authors named "Lena Holmberg"

8 Publications

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Transplantation of Human Neural Precursor Cells Reverses Syrinx Growth in a Rat Model of Post-Traumatic Syringomyelia.

Neurotherapeutics 2021 Jan 19. Epub 2021 Jan 19.

Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Posttraumatic syringomyelia (PTS) is a serious condition of progressive expansion of spinal cord cysts, affecting patients with spinal cord injury years after injury. To evaluate neural cell therapy to prevent cyst expansion and potentially replace lost neurons, we developed a rat model of PTS. We combined contusive trauma with subarachnoid injections of blood, causing tethering of the spinal cord to the surrounding vertebrae, resulting in chronically expanding cysts. The cysts were usually located rostral to the injury, extracanalicular, lined by astrocytes. T2*-weighted magnetic resonance imaging (MRI) showed hyperintense fluid-filled cysts but also hypointense signals from debris and iron-laden macrophages/microglia. Two types of human neural stem/progenitor cells-fetal neural precursor cells (hNPCs) and neuroepithelial-like stem cells (hNESCs) derived from induced pluripotent stem cells-were transplanted to PTS cysts. Cells transplanted into cysts 10 weeks after injury survived at least 10 weeks, migrated into the surrounding parenchyma, but did not differentiate during this period. The cysts were partially obliterated by the cells, and cyst walls often merged with thin layers of cells in between. Cyst volume measurements with MRI showed that the volumes continued to expand in sham-transplanted rats by 102%, while the cyst expansion was effectively prevented by hNPCs and hNESCs transplantation, reducing the cyst volumes by 18.8% and 46.8%, respectively. The volume reductions far exceeded the volume of the added human cells. Thus, in an animal model closely mimicking the clinical situation, we provide proof-of-principle that transplantation of human neural stem/progenitor cells can be used as treatment for PTS.
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http://dx.doi.org/10.1007/s13311-020-00987-3DOI Listing
January 2021

Correction to: Human ex vivo spinal cord slice culture as a useful model of neural development, lesion, and allogeneic neural cell therapy.

Stem Cell Res Ther 2020 Aug 27;11(1):369. Epub 2020 Aug 27.

Department of Neurobiology, Care Sciences and Society, Div. of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13287-020-01893-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450545PMC
August 2020

Human ex vivo spinal cord slice culture as a useful model of neural development, lesion, and allogeneic neural cell therapy.

Stem Cell Res Ther 2020 07 29;11(1):320. Epub 2020 Jul 29.

Department of Neurobiology, Care Sciences and Society, Div. of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.

Background: There are multiple promising treatment strategies for central nervous system trauma and disease. However, to develop clinically potent and safe treatments, models of human-specific conditions are needed to complement in vitro and in vivo animal model-based studies.

Methods: We established human brain stem and spinal cord (cross- and longitudinal sections) organotypic cultures (hOCs) from first trimester tissues after informed consent by donor and ethical approval by the Regional Human Ethics Committee, Stockholm (lately referred to as Swedish Ethical Review Authority), and The National Board of Health and Welfare, Sweden. We evaluated the stability of hOCs with a semi-quantitative hOC score, immunohistochemistry, flow cytometry, Ca signaling, and electrophysiological analysis. We also applied experimental allogeneic human neural cell therapy after injury in the ex vivo spinal cord slices.

Results: The spinal cord hOCs presented relatively stable features during 7-21 days in vitro (DIV) (except a slightly increased cell proliferation and activated glial response). After contusion injury performed at 7 DIV, a significant reduction of the hOC score, increase of the activated caspase-3 cell population, and activated microglial populations at 14 days postinjury compared to sham controls were observed. Such elevation in the activated caspase-3 population and activated microglial population was not observed after allogeneic human neural cell therapy.

Conclusions: We conclude that human spinal cord slice cultures have potential for future structural and functional studies of human spinal cord development, injury, and treatment strategies.
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http://dx.doi.org/10.1186/s13287-020-01771-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390865PMC
July 2020

A sensitive and reliable test instrument to assess swimming in rats with spinal cord injury.

Behav Brain Res 2015 Sep 16;291:172-183. Epub 2015 May 16.

Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Stockholms Sjukhem Foundation, Stockholm, Sweden. Electronic address:

For clinical translation of experimental spinal cord injury (SCI) research, evaluation of animal SCI models should include several sensorimotor functions. Validated and reliable assessment tools should be applicable to a wide range of injury severity. The BBB scale is the most widely used test instrument, but similar to most others it is used to assess open field ambulation. We have developed an assessment tool for swimming in rats with SCI, with high discriminative power and sensitivity to functional recovery after mild and severe injuries, without need for advanced test equipment. We studied various parameters of swimming in four groups of rats with thoracic SCI of different severity and a control group, for 8 weeks after surgery. Six parameters were combined in a multiple item scale, the Karolinska Institutet Swim Assessment Tool (KSAT). KSAT scores for all SCI groups showed consistent functional improvement after injury, and significant differences between the five experimental groups. The internal consistency, the inter-rater and the test-retest reliability were very high. The KSAT score was highly correlated to the cross-section area of white matter spared at the injury epicenter. Importantly, even after 8 weeks of recovery the KSAT score reliably discriminated normal animals from those inflicted by the mildest injury, and also displayed the recovery of the most severely injured rats. We conclude that this swim scale is an efficient and reliable tool to assess motor activity during swimming, and an important addition to the methods available for evaluating rat models of SCI.
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http://dx.doi.org/10.1016/j.bbr.2015.05.004DOI Listing
September 2015

Neuroprotective effects of human spinal cord-derived neural precursor cells after transplantation to the injured spinal cord.

Exp Neurol 2014 Mar 8;253:138-45. Epub 2014 Jan 8.

Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Geriatric Clinic Res Lab., Novum, S-14186 Stockholm, Sweden; Stockholms Sjukhem Foundation, Mariebergsgatan 22, S-11235 Stockholm, Sweden. Electronic address:

To validate human neural precursor cells (NPCs) as potential donor cells for transplantation therapy after spinal cord injury (SCI), we investigated the effect of NPCs, transplanted as neurospheres, in two different rat SCI models. Human spinal cord-derived NPCs (SC-NPCs) transplanted 9 days after spinal contusion injury enhanced hindlimb recovery, assessed by the BBB locomotor test. In spinal compression injuries, SC-NPCs transplanted immediately or after 1 week, but not 7 weeks after injury, significantly improved hindlimb recovery compared to controls. We could not detect signs of mechanical allodynia in transplanted rats. Four months after transplantation, we found more human cells in the host spinal cord than were transplanted, irrespective of the time of transplantation. There was no focal tumor growth. In all groups the vast majority of NPCs differentiated into astrocytes. Importantly, the number of surviving rat spinal cord neurons was highest in groups transplanted acutely and subacutely, which also showed the best hindlimb function. This suggests that transplanted SC-NPCs improve the functional outcome by a neuroprotective effect. We conclude that SC-NPCs reliably enhance the functional outcome after SCI if transplanted acutely or subacutely, without causing allodynia. This therapeutic effect is mainly the consequence of a neuroprotective effect of the SC-NPCs.
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http://dx.doi.org/10.1016/j.expneurol.2013.12.022DOI Listing
March 2014

[Reduced number of home visits in child health care. Nurses' attitudes determine the development of the service].

Lakartidningen 2010 Nov 24-30;107(47):2968-71

Barnhälsovårdsteamet, Halmstad.

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January 2011

Human neural precursor cells continue to proliferate and exhibit low cell death after transplantation to the injured rat spinal cord.

Brain Res 2009 Jun 17;1278:15-26. Epub 2009 Apr 17.

Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Geriatric Clinic Res. Lab., Novum level 5, Stockholm, Sweden.

During the last decade, the interest in stem and progenitor cells, and their applications in spinal cord injuries have steadily increased. However, little is known about proliferation and cell death mechanisms in these cells after transplantation to the spinal cord. The aim of the present project was to study cell turn-over, i.e. total cell number, with time course of proliferation and cell death, in human neural precursor cells (NPCs) after transplantation to the injured rat spinal cord. Immunodeficient rats were subjected to lateral clip compression injuries, transplanted with neurospheres of human forebrain-derived NPCs two weeks after lesion, and sacrificed after 6 h, 1, 3, 10, or 21 days. Cell death was assessed by quantifying human cells immunoreactive for active caspase-3 and calpain 1-dependent fodrin breakdown products (FBDP). The results showed that after an initial drop, the number of implanted cells increased over time after transplantation. Cell proliferation was substantial, with 34% of human cells being immunoreactive for proliferating cell nuclear antigen at 6 h, but which declined over the next few days. The fractions of caspase-3-, and FBDP-immunoreactive cells were remarkably low, together representing 18% of all human cells at 6 h, and rapidly decreasing the next few days. Our results show that already 10 days after spinal cord transplantation of human NPCs as intact neurospheres, the number of human cells exceeded the initially implanted, which was the result of marked cell proliferation in combination with a low rate of apoptotic and non-apoptotic cell death taking place early after transplantation.
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http://dx.doi.org/10.1016/j.brainres.2009.04.012DOI Listing
June 2009

Long-term culture and neuronal survival after intraspinal transplantation of human spinal cord-derived neurospheres.

Physiol Behav 2007 Sep 25;92(1-2):60-6. Epub 2007 May 25.

Karolinska Institutet, Division of Neurodegeneration and Neuroinflammation, Department of Neurobiology, Care Sciences and Society, Novum, S-141 86 Stockholm, Sweden.

There is heterogeneity in neural stem and progenitor cell characteristics depending on their species and regional origin. In search for potent in vitro-expanded human neural precursor cells and cell therapy methods to repair the injured human spinal cord, the possible influence exerted by intrinsic cellular heterogeneity has to be considered. Data available on in vitro-expanded human spinal cord-derived cells are sparse and it has previously been difficult to establish long-term neurosphere cultures showing multipotentiality. In the present paper, human spinal cord-derived neurospheres were cultured in the presence of EGF, bFGF and CNTF for up to 25 passages (>350 days) in vitro. In contrast to the human first trimester subcortical forebrain, spinal cord tissue>9.5 weeks of gestation could not serve as a source for long-term neurosphere cultures under the present conditions. After withdrawal of mitogens, cultured neurospheres (at 18 passages) gave rise to cells with neuronal, astrocytic and oligodendrocytic phenotypes in vitro. After transplantation of human spinal cord-derived neurospheres to the lesioned spinal cord of immuno-deficient adult rats, large numbers of cells survived at least up to 6 weeks, expressing neuronal and astrocytic phenotypes. These results demonstrate that it is possible to expand and maintain multipotent human spinal cord-derived neurospheres in vitro for extended time-periods and that they have promising in vivo potential after engraftment to the injured spinal cord.
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http://dx.doi.org/10.1016/j.physbeh.2007.05.056DOI Listing
September 2007