Browsing by Subject "REGENERATION"

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  • Ainola, Mari; Tomaszewski, Waclaw; Ostrowska, Barbara; Wesolowska, Ewa; Wagner, H. Daniel; Swieszkowski, Wojciech; Sillat, Tarvo; Peltola, Emilia; Konttinen, Yrjo T. (2016)
    The aim was to develop a hybrid three-dimensional-tissue engineering construct for chondrogenesis. The hypothesis was that they support chondrogenesis. A biodegradable, highly porous polycaprolactone-grate was produced by solid freeform fabrication. The polycaprolactone support was coated with a chitosan/polyethylene oxide nanofibre sheet produced by electrospinning. Transforming growth factor-3-induced chondrogenesis was followed using the following markers: sex determining region Y/-box 9, runt-related transcription factor 2 and collagen II and X in quantitative real-time polymerase chain reaction, histology and immunostaining. A polycaprolactone-grate and an optimized chitosan/polyethylene oxide nanofibre sheet supported cellular aggregation, chondrogenesis and matrix formation. In tissue engineering constructs, the sheets were seeded first with mesenchymal stem cells and then piled up according to the lasagne principle. The advantages of such a construct are (1) the cells do not need to migrate to the tissue engineering construct and therefore pore size and interconnectivity problems are omitted and (2) the cell-tight nanofibre sheet and collagen-fibre network mimic a cell culture platform for mesenchymal stem cells/chondrocytes (preventing escape) and hinders in-growth of fibroblasts and fibrous scarring (preventing capture). This allows time for the slowly progressing, multiphase true cartilage regeneration.
  • Viitanen, Tiina P.; Visuri, Mikko T.; Sulo, Eeva; Saarikko, Anne M.; Hartiala, Pauliina (2015)
    Background: Transfer of healthy tissue is commonly used in the treatment of complicated wounds and in reconstruction of tissue defects. Recently, microvascular lymph node transfer (LN) has been used to improve the lymphatic function in lymphedema patients. To elucidate the biological effects of flap transfer (with and without lymph nodes), we have studied the postoperative production of proinflammatory, anti-inflammatory, prolymphangiogenic and antilymphangiogenic cytokines, and growth factors (interleukin 1 alpha [IL-1 alpha], IL-1 beta, tumor necrosis factor alpha [TNF-alpha], IL-10, transforming growth factor beta 1 [TGF-beta 1], IL-4 and IL-13, and vascular endothelial growth factor C [VEGF-C] and VEGF-D) in postoperative wound exudate samples. Methods: Axillary wound exudate samples were analyzed from four patient groups: axillary lymph node dissection (ALND), microvascular breast reconstruction (BR), LN, and combined LN and BR (LN-BR). Results: The concentration of proinflammatory cytokines was low in all the flap transfer groups as opposed to the ALND group, which showed an extensive proinflammatory response. The level of anti-inflammatory and antifibrotic cytokine IL-10 was increased in the LN-BR group samples compared with the ALND and BR groups. In the LN and LN-BR groups, the cytokine profile showed an anti-inflammatory response. Conclusions: Transfer of healthy tissue hinders the proinflammatory response after surgery, which may explain the beneficial effects of flap transfer in various patient groups. In addition, flap transfer with lymph nodes seems to also promote an antifibrotic effect. The clinical effects of LN in lymphedema patients may be mediated by the increased production of prolymphangiogenic growth factor (VEGF-C) and antifibrotic cytokine (IL-10). (C) 2015 Elsevier Inc. All rights reserved.
  • White, Joanne C.; Saarinen, Ninni; Wulder, Michael A.; Kankare, Ville; Hermosilla, Txomin; Coops, Nicholas C.; Holopainen, Markus; Hyyppä, Juha; Vastaranta, Mikko (2019)
    Information regarding the nature and rate of forest recovery is required to inform forest management, monitoring, and reporting activities. Delayed establishment or return of forests has implications to harvest rotations and carbon uptake, among others, creating a need for spatially-explicit, large-area, characterizations of forest recovery. Landsat time series (LTS) has been demonstrated as a means to quantitatively relate forest recovery, noting that there are gaps in our understanding of the linkage between spectral measures of forest recovery and manifestations of forest structure and composition. Field plots provide a means to better understand the linkage between forest characteristics and spectral recovery indices. As such, from a large set of existing field plots, we considered the conditions present for the year in which the co-located pixel was considered spectrally recovered using the Years to Recovery (Y2R) metric. Y2R is a long-term metric of spectral recovery that indicates the number of years required for a pixel to return to 80% of its pre-disturbance Normalized Burn Ratio value. Absolute and relative metrics of recovery at 5 years post-disturbance were also considered. We used these three spectral recovery metrics to predict the stand development class assigned by the field crew for 284 seedling plots with an overall accuracy of 73.59%, with advanced seedling stands more accurately discriminated (omission error, OE = 15.74%) than young seedling stands (OE = 49.84%). We then used field-measured attributes (e.g. height, stem density, dominant species) from the seedling plots to classify the plots into three spectral recovery groups, which were defined using the Y2R metric: spectral recovery in (1) 1–5 years, (2) 6–10 years, or (3) 11–15 years. Overall accuracy for spectral recovery groups was 61.06%. Recovery groups 1 and 3 were discriminated with greater accuracy (producer’s and user’s accuracies > 66%) than recovery group 2 (<50%). The top field-measured predictors of spectral recovery were mean height, dominant species, and percentage of stems in the plot that were deciduous. Variability in stand establishment and condition make it challenging to accurately discriminate among recovery rates within 10 years post-harvest. Our results indicate that the long-term metric Y2R relates to forest structure and composition attributes measured in the field and that spectral development post-disturbance corresponds with expectations of structural development, particularly height, for different species, site types, and deciduous abundance. These results confirm the utility of spectral recovery measures derived from LTS data to augment landscape-level assessments of post-disturbance recovery.
  • Liu, Dongfei; Chen, Jian; Jiang, Tao; Li, Wei; Huang, Yao; Lu, Xiyi; Liu, Zehua; Zhang, Weixia; Zhou, Zheng; Ding, Qirui; Almeida Santos, Helder; Yin, Guoyong; Fan, Jin (2018)
    New treatment strategies for spinal cord injury with good therapeutic efficacy are actively pursued. Here, acetalated dextran (AcDX), a biodegradable polymer obtained by modifying vicinal diols of dextran, is demonstrated to protect the traumatically injured spinal cord. To facilitate its administration, AcDX is formulated into microspheres (approximate to 7.2 mu m in diameter) by the droplet microfluidic technique. Intrathecally injected AcDX microspheres effectively reduce the traumatic lesion volume and inflammatory response in the injured spinal cord, protect the spinal cord neurons from apoptosis, and ultimately, recover the locomotor function of injured rats. The neuroprotective feature of AcDX microspheres is achieved by sequestering glutamate and calcium ions in cerebrospinal fluid. The scavenging of glutamate and calcium ion reduces the influx of calcium ions into neurons and inhibits the formation of reactive oxygen species. Consequently, AcDX microspheres attenuate the expression of proapoptotic proteins, Calpain, and Bax, and enhance the expression of antiapoptotic protein Bcl-2. Overall, AcDX microspheres protect traumatically injured spinal cord by alleviating the glutamate-induced excitotoxicity. This study opens an exciting perspective toward the application of neuroprotective AcDX for the treatment of severe neurological diseases.
  • Kaarakka, Lilli; Hyvönen, Riitta; Strömgren, Monika; Palviainen, Marjo; Persson, Tryggve; Olsson, Bengt A; Launonen, Erno; Vegerfors, Birgitta; Helmisaari, Heljä-Sisko (2016)
    The use of forest-derived biomass has steadily increased in Finland and Sweden during the past decades leading to more intensive forest management practices in the region, such as whole-tree harvesting, both above- and belowground. Stump harvesting results in a direct removal of stump and coarse-root carbon (C) from the stand and can cause extensive soil disturbance, which has been suggested to increase C mineralization. In this study, the effects of stump harvesting on soil C and nitrogen (N) mineralization, and soil surface disturbance were studied in two different clear-felled Norway spruce (Picea abies) sites in Central Finland. The treatments were whole-tree harvesting (WTH, removal of stems and logging residues), and WTH and stump harvesting (WTH + S). Both sites, Honkola (2 stands) and Haukilahti (6 stands) were mounded. In both treatments, soil samples were taken from different soil layers down to a total depth of 20 cm in the mineral soil from (i) mounds, (ii) undisturbed soil and (iii) pits. The sampling was performed 11-12 years after treatments. Soil C and N mineralization rates were determined in laboratory incubation experiments. In addition, total C and N pools (g m(2)) were estimated for each disturbance class and soil layer. Soil C and N pools had a tendency to be lower following stump harvesting, but no statistically significant treatment effect was detected. Stump harvesting increased soil mixing as indicated by a significant decrease in C concentration in the mound disturbance class. There was no significant effect of stump harvesting on soil C mineralization rates. A combination of mineralization rates and soil pool data showed that field C mineralization (g CO2-C m(-2) yr(-1)) did not significantly differ between stands where stumps were removed or were retained. Further, stump harvesting did not seem to have any stimulating effect on soil CO2 efflux 11-12 years after treatment. (C) 2016 Elsevier B.V. All rights reserved.
  • Pitkänen, S.; Paakinaho, K.; Pihlman, H.; Ahola, N.; Hannula, M.; Asikainen, S.; Manninen, M.; Morelius, M.; Keränen, P.; Hyttinen, J.; Kellomäki, M.; Laitinen-Vapaavuori, O.; Miettinen, S. (2019)
    Most synthetic bone grafts are either hard and brittle ceramics or paste-like materials that differ in applicability from the gold standard autologous bone graft, which restricts their widespread use. Therefore, the aim of the study was to develop an elastic, highly porous and biodegradable beta-tricalciumphosphate/poly(L-lactide-co-epsilon-caprolactone) (beta-TCP/PLCL) composite for bone applications using supercritical CO2 foaming. Ability to support osteogenic differentiation was tested in human adipose stem cell (hASC) culture for 21 d. Biocompatibility was evaluated for 24 weeks in a rabbit femur-defect model. Foamed composites had a high ceramic content (50 wt%) and porosity (65-67 %). After 50 % compression, in an aqueous environment at 37 degrees C, tested samples returned to 95 % of their original height. Hydrolytic degradation of beta-TCP/PLCL composite, during the 24-week follow-up, was very similar to that of porous PLCL scaffold both in vitro and in vivo. Osteogenic differentiation of hASCs was demonstrated by alkaline phosphatase activity analysis, alizarin red staining, soluble collagen analysis, immunocytochemical staining and qRT-PCR. In vitro, hASCs formed a pronounced mineralised collagen matrix. A rabbit femur defect model confirmed biocompatibility of the composite. According to histological Masson-Goldner's trichrome staining and micro-computed tomography, beta-TCP/PLCL composite did not elicit infection, formation of fibrous capsule or cysts. Finally, native bone tissue at 4 weeks was already able to grow on and in the beta-TCP/PLCL composite. The elastic and highly porous beta-TCP/PLCL composite is a promising bone substitute because it is osteoconductive and easy-to-use and mould intraoperatively.
  • Imangholiloo, Mohammad; Saarinen, Ninni; Markelin, Lauri; Rosnell, Tomi; Nasi, Roope; Hakala, Teemu; Honkavaara, Eija; Holopainen, Markus; Hyyppa, Juha; Vastaranta, Mikko (2019)
    Seedling stands are mainly inventoried through field measurements, which are typically laborious, expensive and time-consuming due to high tree density and small tree size. In addition, operationally used sparse density airborne laser scanning (ALS) and aerial imagery data are not sufficiently accurate for inventorying seedling stands. The use of unmanned aerial vehicles (UAVs) for forestry applications is currently in high attention and in the midst of quick development and this technology could be used to make seedling stand management more efficient. This study was designed to investigate the use of UAV-based photogrammetric point clouds and hyperspectral imagery for characterizing seedling stands in leaf-off and leaf-on conditions. The focus was in retrieving tree density and the height in young seedling stands in the southern boreal forests of Finland. After creating the canopy height model from photogrammetric point clouds using national digital terrain model based on ALS, the watershed segmentation method was applied to delineate the tree canopy boundary at individual tree level. The segments were then used to extract tree heights and spectral information. Optimal bands for calculating vegetation indices were analysed and used for species classification using the random forest method. Tree density and the mean tree height of the total and spruce trees were then estimated at the plot level. The overall tree density was underestimated by 17.5% and 20.2% in leaf-off and leaf-on conditions with the relative root mean square error (relative RMSE) of 33.5% and 26.8%, respectively. Mean tree height was underestimated by 20.8% and 7.4% (relative RMSE of 23.0% and 11.5%, and RMSE of 0.57 m and 0.29 m) in leaf-off and leaf-on conditions, respectively. The leaf-on data outperformed the leaf-off data in the estimations. The results showed that UAV imagery hold potential for reliably characterizing seedling stands and to be used to supplement or replace the laborious field inventory methods.
  • Poczai, Peter; Santiago-Blay, Jorge A. (2022)
    Heredity is such a fundamental concept that it is hard to imagine a world where the connection between parents and offspring is not understood. Three hundred years ago thinking of the phenomenon of heredity bore on a cluster of distinct philosophical questions inherited from antiquity concerning the nature and origin of substances or beings that lacked biological meaning. We are reminded of this philosophical heritage by the fact that in the 18th century the study of reproduction, embryology and development was referred to as "the science of generation". It is now clear that reproduction, the biological process by which parents produce offspring, is a fundamental feature of all life on Earth. Heredity, the transmission of traits from parents to offspring via sexual or asexual reproduction, allows differences between individuals to accumulate and evolve through natural selection. Genetics is the study of heredity, and in particular, variation of fundamental units responsible for heredity. Ideas underlying this theory evolved in considerably different and unrelated ways across a number of knowledge domains, including philosophy, medicine, natural history, and breeding. The fusion of these different domains into a single comprehensive theory in 19th century biology was a historically and culturally interdependent process, thus examining genetic prehistory should unravel these entanglements. The major goal of our review is tracing the various threads of thought that gradually converged into our contemporary understanding of heredity.
  • Hong, Seon Pyo; Yang, Myung Jin; Cho, Hyunsoo; Park, Intae; Bae, Hosung; Choe, Kibaek; Suh, Sang Heon; Adams, Ralf H.; Alitalo, Kari; Lim, Daesik; Koh, Gou Young (2020)
    Emerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFR beta(+) IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.
  • Sundvik, Maria; Nieminen, Heikki J.; Salmi, Ari; Panula, Pertti; Haeggstrom, Edward (2015)
    Acoustic levitation provides potential to characterize and manipulate material such as solid particles and fluid in a wall-less environment. While attempts to levitate small animals have been made, the biological effects of such levitation have been scarcely documented. Here, our goal was to explore if zebrafish embryos can be levitated (peak pressures at the pressure node and anti-node: 135 dB and 144 dB, respectively) with no effects on early development. We levitated the embryos (n = 94) at 2-14 hours post fertilization (hpf) for 1000 (n = 47) or 2000 seconds (n = 47). We compared the size and number of trunk neuromasts and otoliths in sonicated samples to controls (n = 94), and found no statistically significant differences (p > 0.05). While mortality rate was lower in the control group (22.3%) compared to that in the 1000 s (34.0%) and 2000 s (42.6%) levitation groups, the differences were statistically insignificant (p > 0.05). The results suggest that acoustic levitation for less than 2000 sec does not interfere with the development of zebrafish embryos, but may affect mortality rate. Acoustic levitation could potentially be used as a non-contacting wall-less platform for characterizing and manipulating vertebrae embryos without causing major adverse effects to their development.
  • Kivelä, Riikka; Hemanthakumar, Karthik Amudhala; Vaparanta, Katri; Robciuc, Marius; Izumiya, Yasuhiro; Kidoya, Hiroyasu; Takakura, Nobuyuki; Peng, Xuyang; Sawyer, Douglas B.; Elenius, Klaus; Walsh, Kenneth; Alitalo, Kari (2019)
    Background: Heart failure, which is a major global health problem, is often preceded by pathological cardiac hypertrophy. The expansion of the cardiac vasculature, to maintain adequate supply of oxygen and nutrients, is a key determinant of whether the heart grows in a physiological compensated manner or a pathological decompensated manner. Bidirectional endothelial cell (EC)-cardiomyocyte (CMC) cross talk via cardiokine and angiocrine signaling plays an essential role in the regulation of cardiac growth and homeostasis. Currently, the mechanisms involved in the EC-CMC interaction are not fully understood, and very little is known about the EC-derived signals involved. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how ECs regulate CMC homeostasis could provide novel therapeutic targets for heart failure. Methods: Genetic mouse models were used to delete vascular endothelial growth factor (VEGF) receptors, adeno-associated viral vectors to transduce the myocardium, and pharmacological inhibitors to block VEGF and ErbB signaling in vivo. Cell culture experiments were used for mechanistic studies, and quantitative polymerase chain reaction, microarrays, ELISA, and immunohistochemistry were used to analyze the cardiac phenotypes. Results: Both EC deletion of VEGF receptor (VEGFR)-1 and adeno-associated viral vector-mediated delivery of the VEGFR1-specific ligands VEGF-B or placental growth factor into the myocardium increased the coronary vasculature and induced CMC hypertrophy in adult mice. The resulting cardiac hypertrophy was physiological, as indicated by preserved cardiac function and exercise capacity and lack of pathological gene activation. These changes were mediated by increased VEGF signaling via endothelial VEGFR2, because the effects of VEGF-B and placental growth factor on both angiogenesis and CMC growth were fully inhibited by treatment with antibodies blocking VEGFR2 or by endothelial deletion of VEGFR2. To identify activated pathways downstream of VEGFR2, whole-genome transcriptomics and secretome analyses were performed, and the Notch and ErbB pathways were shown to be involved in transducing signals for EC-CMC cross talk in response to angiogenesis. Pharmacological or genetic blocking of ErbB signaling also inhibited part of the VEGF-B-induced effects in the heart. Conclusions: This study reveals that cross talk between the EC VEGFR2 and CMC ErbB signaling pathways coordinates CMC hypertrophy with angiogenesis, contributing to physiological cardiac growth.
  • Xie, Yanbo; Lampinen, Milla; Takala, Juuso; Sikorski, Vilbert; Soliymani, Rabah; Tarkia, Miikka; Lalowski, Maciej; Mervaala, Eero; Kupari, Markku; Zheng, Zhe; Hu, Shengshou; Harjula, Ari; Kankuri, Esko (2020)
    BACKGROUND Ischemic heart disease remains the leading cause of mortality and morbidity worldwide despite improved possibilities in medical care. Alongside interventional therapies, such as coronary artery bypass grafting, adjuvant tissue-engineered and cell-based treatments can provide regenerative improvement. Unfortunately, most of these advanced approaches require multiple lengthy and costly preparation stages without delivering significant clinical benefits. METHODS We evaluated the effect of epicardially delivered minute pieces of atrial appendage tissue material, defined as atrial appendage micrografts (AAMs), in mouse myocardial infarction model. An extracellular matrix patch was used to cover and fix the AAMs onto the surface of the infarcted heart. RESULTS The matrix-covered AAMs salvaged the heart from infarction-induced loss of functional myocardium and attenuated scarring. Site-selective proteomics of injured ischemic and uninjured distal myocardium from AAMs-treated and untreated tissue sections revealed an increased expression of several cardiac regeneration-associated proteins (i.e. periostin, transglutaminases and glutathione peroxidases) as well as activation of pathways responsible for angio- and cardiogenesis in relation to AAMs therapy. CONCLUSIONS Epicardial delivery of AAMs encased in an extracellular matrix patch scaffold salvages functional cardiac tissue from ischemic injury and restricts fibrosis after myocardial infarction. Our results support the use of AAMs as tissue-based therapy adjuvants for salvaging the ischemic myocardium.
  • Mihaylova, Maria M.; Cheng, Chia-Wei; Cao, Amanda Q.; Tripathi, Surya; Mana, Miyeko D.; Bauer-Rowe, Khristian E.; Abu-Remaileh, Monther; Clavain, Laura; Erdemir, Aysegul; Lewis, Caroline A.; Freinkman, Elizaveta; Dickey, Audrey S.; La Spada, Albert R.; Huang, Yanmei; Bell, George W.; Deshpande, Vikram; Carmeliet, Peter; Katajisto, Pekka; Sabatini, David M.; Yilmaz, Ömer H. (2018)
    Diet has a profound effect on tissue regeneration in diverse organisms, and low caloric states such as intermittent fasting have beneficial effects on organismal health and age-associated loss of tissue function. The role of adult stem and progenitor cells in responding to short-term fasting and whether such responses improve regeneration are not well studied. Here we show that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting. Acute genetic disruption of Cpt1a, the rate-limiting enzyme in FAO, abrogates ISC-enhancing effects of fasting, but long-term Cpt1a deletion decreases ISC numbers and function, implicating a role for FAO in ISC maintenance. These findings highlight a role for FAO in mediating pro-regenerative effects of fasting in intestinal biology, and they may represent a viable strategy for enhancing intestinal regeneration.
  • Salonius, Eve; Muhonen, Virpi; Lehto, Kalle; Järvinen, Elina; Pyhältö, Tuomo; Hannula, Markus; Aula, Antti S.; Uppstu, Peter; Haaparanta, Anne-Marie; Rosling, Ari; Kellomäki, Minna; Kiviranta, Ilkka (2019)
    Deep osteochondral defects may leave voids in the subchondral bone, increasing the risk of joint structure collapse. To ensure a stable foundation for the cartilage repair, bone grafts can be used for filling these defects. Poly(lactide-co-glycolide) (PLGA) is a biodegradable material that improves bone healing and supports bone matrix deposition. We compared the reparative capacity of two investigative macroporous PLGA-based biomaterials with two commercially available bone graft substitutes in the bony part of an intra-articular bone defect created in the lapine femur. New Zealand white rabbits (n = 40) were randomized into five groups. The defects, 4 mm in diameter and 8 mm deep, were filled with neat PLGA; a composite material combining PLGA and bioactive glass fibres (PLGA-BGf); commercial beta-tricalcium phosphate (beta-TCP) granules; or commercial bioactive glass (BG) granules. The fifth group was left untreated for spontaneous repair. After three months, the repair tissue was evaluated with X-ray microtomography and histology. Relative values comparing the operated knee with its contralateral control were calculated. The relative bone volume fraction ( increment BV/TV) was largest in the beta-TCP group (p
  • Chen, Wei; Chen, Hao; Zheng, Dandan; Zhang, Hongbo; Deng, Lianfu; Cui, Wenguo; Zhang, Yuhui; Santos, Hélder A.; Shen, Hongxing (2020)
    Gene therapy provides an ideal potential treatment for intervertebral disk degeneration by delivering synthetic microRNAs (miRNAs) to regulate the gene expression levels. However, it is very challenging to deliver miRNAs directly, which leads to inactivation, low transfection efficiency, and short half‐life. Here, Agomir is loaded in hydrogel to construct a gene‐hydrogel microenvironment for regulating the synthesis/catabolism balance of the tissue extracellular matrix (ECM) to treat degenerative diseases. Agomir is a cholesterol‐, methylation‐, and phosphorothioate‐modified miRNA, which can mimic the function of miRNA to regulate the expression of the target gene. Agomir874 that mimics miRNA874 is synthesized to down regulate the expression of matrix metalloproteinases (MMPs) in nucleus pulposus (NP). At the same time, a polyethylene glycol (PEG) hydrogel is synthesized through Ag‐S coordination of 4‐arm PEG‐SH and silver ion solution, which has injectable, self‐healing, antimicrobial, degradable, and superabsorbent properties and matches perfectly with the mechanism of intervertebral disk. By delivering Agomir‐loaded PEG‐hydrogel to a degenerative intervertebral disk, a gene‐hydrogel microenvironment is constructed in situ, which reduces the expression of MMPs, regulates the synthesis/catabolism balance of ECM in the NP of the intervertebral disk, and improves the tissue microenvironment regeneration.
  • Suh, Sang Heon; Choe, Kibaek; Hong, Seon Pyo; Jeong, Seung-hwan; Mäkinen, Taija; Kim, Kwang Soon; Alitalo, Kari; Surh, Charles D.; Koh, Gou Young; Song, Joo-Hye (2019)
    A lacteal is a blunt-ended, long, tube-like lymphatic vessel located in the center of each intestinal villus that provides a unique route for drainage of absorbed lipids from the small intestine. However, key regulators for maintaining lacteal integrity are poorly understood. Here, we explore whether and how the gut microbiota regulates lacteal integrity. Germ depletion by antibiotic treatment triggers lacteal regression during adulthood and delays lacteal maturation during the postnatal period. In accordance with compromised lipid absorption, the button-like junction between lymphatic endothelial cells, which is ultrastructurally open to permit free entry of dietary lipids into lacteals, is significantly reduced in lacteals of germ-depleted mice. Lacteal defects are also found in germ-free mice, but conventionalization of germ-free mice leads to normalization of lacteals. Mechanistically, VEGF-C secreted from villus macrophages upon MyD88-dependent recognition of microbes and their products is a main factor in lacteal integrity. Collectively, we conclude that the gut microbiota is a crucial regulator for lacteal integrity by endowing its unique microenvironment and regulating villus macrophages in small intestine.
  • Kulesskaya, Natalia; Molotkov, Dmitry; Sliepen, Sonny; Mugantseva, Ekaterina; Garcia Horsman, Arturo; Paveliev, Mikhail; Rauvala, Heikki (2021)
    Heparin-binding growth-associated molecule (pleiotrophin) is a neurite outgrowth-promoting secretory protein that lines developing fiber tracts in juvenile CNS (central nervous system). Previously, we have shown that heparin-binding growth-associated molecule (HB-GAM) reverses the CSPG (chondroitin sulfate proteoglycan) inhibition on neurite outgrowth in the culture medium of primary CNS neurons and enhances axon growth through the injured spinal cord in mice demonstrated by two-photon imaging. In this study, we have started studies on the possible role of HB-GAM in enhancing functional recovery after incomplete spinal cord injury (SCI) using cervical lateral hemisection and hemicontusion mouse models. In vivo imaging of blood-oxygen-level-dependent (BOLD) signals associated with functional activity in the somatosensory cortex was used to assess the sensory functions during vibrotactile hind paw stimulation. The signal displays an exaggerated response in animals with lateral hemisection that recovers to the level seen in the sham-operated mice by injection of HB-GAM to the trauma site. The effect of HB-GAM treatment on sensory-motor functions was assessed by performance in demanding behavioral tests requiring integration of afferent and efferent signaling with central coordination. Administration of HB-GAM either by direct injection into the trauma site or by intrathecal injection improves the climbing abilities in animals with cervical hemisection and in addition enhances the grip strength in animals with lateral hemicontusion without affecting the spontaneous locomotor activity. Recovery of sensory signaling in the sensorimotor cortex by HB-GAM to the level of sham-operated mice may contribute to the improvement of skilled locomotion requiring integration of spatiotemporal signals in the somatosensory cortex.
  • Lagus, Heli; Kankuri, Esko; Nuutila, Kristo; Juteau, Susanna; Sarlomo-Rikala, Maarit; Vuola, Jyrki (2018)
    Cellular grafts used for skin repair require rapid integration with the host tissue to remain viable and especially to nourish the epidermal cells. Here, we evaluated the responses in the split-thickness skin grafts (STSGs) grafted on three differently treated wound beds: directly on excised wound bed (EX), on an artificial dermal template (DT) and on granulation tissue (GT) induced by cellulose sponge. In ten burn patients, after excision, a test area was divided into three sections: One transplanted with STSG instantaneously and two sections had a pre-treatment for 2 weeks with either DT or a cellulose sponge inducing granulation tissue formation and thereafter grafted with STSGs. One week after grafting, the STSGs on GT demonstrated most endothelial CD31(+) staining, largest average vessel diameters as well as most CD163(+) staining of M2-like macrophages and most MIB1(+) proliferating epidermal cells, suggesting an active regenerative environment. STSGs on DT had smallest vessel diameters and the least CD163(+) macrophages. STSGs on EX had the least CD31(+) cells and the least MIB1(+) proliferating cells. After 3 months, this reactivity in STSGs had subsided, except increased dermal cell proliferation was observed in STSGs on EX. Results show that pre-treatment of wound bed and induction of granulation tissue formation can accelerate host-graft interaction by stimulating graft vasculature and inducing cell proliferation.
  • Talman, Virpi; Teppo, Jaakko Sakari; Pöhö, Päivi Anneli; Movahedi, Parisa; Vaikkinen, Anu; Karhu, Suvi Tuuli; Trošt, Kajetan; Suvitaival, Tommi; Heikkonen, Jukka; Pahikkala, Tapio; Kotiaho, Ahti Antti Tapio; Kostiainen, Risto Kalervo; Varjosalo, Markku Tapio; Ruskoaho, Heikki Juhani (2018)
    Background The molecular mechanisms mediating postnatal loss of cardiac regeneration in mammals are not fully understood. We aimed to provide an integrated resource of mRNA, protein, and metabolite changes in the neonatal heart for identification of metabolism‐related mechanisms associated with cardiac regeneration. Methods and Results Methods and results Mouse ventricular tissue samples taken on postnatal day 1 (P01), P04, P09, and P23 were analyzed with RNA sequencing and global proteomics and metabolomics. Gene ontology analysis, KEGG pathway analysis, and fuzzy c‐means clustering were used to identify up‐ or downregulated biological processes and metabolic pathways on all 3 levels, and Ingenuity pathway analysis (Qiagen) was used to identify upstream regulators. Differential expression was observed for 8547 mRNAs and for 1199 of 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Differentially regulated metabolic pathways include branched chain amino acid degradation (upregulated at P23), fatty acid metabolism (upregulated at P04 and P09; downregulated at P23) as well as the HMGCS (HMG‐CoA [hydroxymethylglutaryl‐coenzyme A] synthase)–mediated mevalonate pathway and ketogenesis (transiently activated). Pharmacological inhibition of HMGCS in primary neonatal cardiomyocytes reduced the percentage of BrdU‐positive cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating the cardiomyocyte cell cycle. Conclusions This study is the first systems‐level resource combining data from genomewide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses in the mouse heart throughout the early postnatal period. These integrated data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies
  • Hungarian Pancreatic Study Grp; Szentesi, Andrea; Parniczky, Andrea; Vincze, Aron; Sallinen, Ville; Hegyi, Peter (2019)
    Introduction: The incidence of acute pancreatitis (AP) and the prevalence of metabolic syndrome (MetS) are growing worldwide. Several studies have confirmed that obesity (OB), hyperlipidemia (HL), or diabetes mellitus (DM) can increase severity, mortality, and complications in AP. However, there is no comprehensive information on the independent or joint effect of MetS components on the outcome of AP. Our aims were (1) to understand whether the components of MetS have an independent effect on the outcome of AP and (2) to examine the joint effect of their combinations. Methods: From 2012 to 2017, 1435 AP cases from 28 centers were included in the prospective AP Registry. Patient groups were formed retrospectively based on the presence of OB, HL, DM, and hypertension (HT). The primary endpoints were mortality, severity, complications of AP, and length of hospital stay. Odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Results: 1257 patients (55.7 +/- 17.0 years) were included in the analysis. The presence of OB was an independent predictive factor for renal failure [OR: 2.98 (CI: 1.33-6.66)] and obese patients spent a longer time in hospital compared to non-obese patients (12.1 vs. 10.4 days, p = 0.008). HT increased the risk of severe AP [OR: 3.41 (CI: 1.39-8.37)], renal failure [OR: 7.46 (CI: 1.61-34.49)], and the length of hospitalization (11.8 vs. 10.5 days, p = 0.020). HL increased the risk of local complications [OR: 1.51 (CI: 1.10-2.07)], renal failure [OR: 6.4 (CI: 1.93-21.17)], and the incidence of newly diagnosed DM [OR: 2.55 (CI: 1.26-5.19)]. No relation was found between the presence of DM and the outcome of AP. 906 cases (mean age +/- SD: 56.9 +/- 16.7 years) had data on all four components of MetS available. The presence of two, three, or four MetS factors increased the incidence of an unfavorable outcome compared to patients with no MetS factors. Conclusion: OB, HT, and HL are independent risk factors for a number of complications. HT is an independent risk factor for severity as well. Components of MetS strongly synergize each other's detrimental effect. It is important to search for and follow up on the components of MetS in AP.