Raoul Kuiper

Bio: Raoul Kuiper is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Transgene & Cancer. The author has an hindex of 15, co-authored 40 publications receiving 1061 citations. Previous affiliations of Raoul Kuiper include Utrecht University & Karolinska University Hospital.

Clonal culturing of human embryonic stem cells on laminin-521/E-cadherin matrix in defined and xeno-free environment

Abstract: Lack of robust methods for establishment and expansion of pluripotent human embryonic stem (hES) cells still hampers development of cell therapy. Laminins (LN) are a family of highly cell-type specific basement membrane proteins important for cell adhesion, differentiation, migration and phenotype stability. Here we produce and isolate a human recombinant LN-521 isoform and develop a cell culture matrix containing LN-521 and E-cadherin, which both localize to stem cell niches in vivo. This matrix allows clonal derivation, clonal survival and long-term self-renewal of hES cells under completely chemically defined and xeno-free conditions without ROCK inhibitors. Neither LN-521 nor E-cadherin alone enable clonal survival of hES cells. The LN-521/E-cadherin matrix allows hES cell line derivation from blastocyst inner cell mass and single blastomere cells without a need to destroy the embryo. This method can facilitate the generation of hES cell lines for development of different cell types for regenerative medicine purposes.

Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice

Abstract: Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1∆/-) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg-/- (also known as Ercc5-/-) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1∆/- mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1∆/- mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1∆/- mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.

Real-time assessment of tissue hypoxia in vivo with combined photoacoustics and high-frequency ultrasound.

Abstract: Purpose: In preclinical cancer studies, non-invasive functional imaging has become an important tool to assess tumor development and therapeutic effects Tumor hypoxia is closely associated with tumor aggressiveness and is therefore a key parameter to be monitored Recently, photoacoustic (PA) imaging with inherently co-registered high-frequency ultrasound (US) has reached preclinical applicability, allowing parallel collection of anatomical and functional information Dual-wavelength PA imaging can be used to quantify tissue oxygen saturation based on the absorbance spectrum differences between hemoglobin and deoxyhemoglobin Experimental Design: A new bi-modal PA/US system for small animal imaging was employed to test feasibility and reliability of dual-wavelength PA for measuring relative tissue oxygenation Murine models of pancreatic and colon cancer were imaged, and differences in tissue oxygenation were compared to immunohistochemistry for hypoxia in the corresponding tissue regions Results: Functional studies proved feasibility and reliability of oxygenation detection in murine tissue in vivo Tumor models exhibited different levels of hypoxia in localized regions, which positively correlated with immunohistochemical staining for hypoxia Contrast-enhanced imaging yielded complementary information on tissue perfusion using the same system Conclusion: Bimodal PA/US imaging can be utilized to reliably detect hypoxic tumor regions in murine tumor models, thus providing the possibility to collect anatomical and functional information on tumor growth and treatment response live in longitudinal preclinical studies

Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth

Abstract: A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer

Abstract: The nonradiative conversion of light energy into heat (photothermal therapy, PTT) or sound energy (photoacoustic imaging, PAI) has been intensively investigated for the treatment and diagnosis of cancer, respectively. By taking advantage of nanocarriers, both imaging and therapeutic functions together with enhanced tumour accumulation have been thoroughly studied to improve the pre-clinical efficiency of PAI and PTT. In this review, we first summarize the development of inorganic and organic nano photothermal transduction agents (PTAs) and strategies for improving the PTT outcomes, including applying appropriate laser dosage, guiding the treatment via imaging techniques, developing PTAs with absorption in the second NIR window, increasing photothermal conversion efficiency (PCE), and also increasing the accumulation of PTAs in tumours. Second, we introduce the advantages of combining PTT with other therapies in cancer treatment. Third, the emerging applications of PAI in cancer-related research are exemplified. Finally, the perspectives and challenges of PTT and PAI for combating cancer, especially regarding their clinical translation, are discussed. We believe that PTT and PAI having noteworthy features would become promising next-generation non-invasive cancer theranostic techniques and improve our ability to combat cancers.

Chemically defined generation of human cardiomyocytes

Abstract: A simple, robust, chemically defined method for generating cardiomyocytes from human pluripotent stem cells is described. It should enable the identification of conditions for maturation of these cells.

Sarcopenia: Aging-Related Loss of Muscle Mass and Function.

Abstract: Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and ex...