Karp, J. M. & Leng Teo, G. S. Mesenchymal stem cell homing: the devil is in the details. For example, if using a dose of 1 U kg -1 , a concentration of 0.2 U ml -1 is suitable. Provided by the Springer Nature SharedIt content-sharing initiative. In another Phase I clinical trial, patients with ovarian cancer were injected intraperitoneally with dl1520 in order to study the effects of a replication-competent/-selective virus. In the guinea pig, the oral LD 50 value is 10 700 mg kg 1. Roddy, G. W. et al. Currently, the intravenous injection (IV) is historically most common methods for MSCs delivery12. Once the animal is properly restrained (as described above for SC injections) the injection site is . Sala, E. et al. Figure 1. Importantly, we identified different migration fates of MSCs and traced their ultimate location of three administration ways for the first time. In anal injection group, same amount of cells were suspended in 200L diluted Matrigel in PBS (1:20) and the cell suspension was instilled into colonic lumen by a syringe with flexible catheter 4cm in length and 2mm in diameter, according to the previous study64. Direct injection of sodium pentobarbital (referred to as euthanasia by . Blood 118, 330338, doi: 10.1182/blood-2010-12-327353 (2011). On the contrary, the most significant advantage of IP and AI routes is that cells do not immediately enter to the blood flow, allowing sufficient blood dilution. PubMed Stem cell transplantation showed promising results in IBD management. Sci Rep 6, 30696 (2016). Firstly, peritoneal cavity provides an isolated, hemodynamically stable, sterile and nutritious environment with enough growth spaces, which are very critical factors for aggregates forming. ADS Because labeled cells are founded in Peyers patch of the gut and peripheral blood, they proposed the most likely routes might be by both lymph- and blood circulation. We selected the day 3 as observation time point. CAS . DSS only served as control. 4 The scalp was disinfected and a midline incision was made in the skin. Intraosseous. On the contrary, the IP and AI groups showed more engraftment cells at the inflamed colon but showed fewer trapped cells in lung, liver and spleen (Fig. injections. The serum concentration of TNFinduced protein 6 (TSG-6) was measured in DSS colitic mice at 48 and 72hours after different routes of MSCs administrations. Since that time, the literatures using stem cells for IBD have expanded. The excitation/ emission spectrum of DiR is in the near infrared range (excitation 750nm and emission 782nm). Very few reports pay attention to factors applied in the clinic, such as injection or exposure routes, which has highly impact on stem cell therapeutic efficiency for IBD12. Cosnes, J., Gower-Rousseau, C., Seksik, P. & Cortot, A. government site. Get the most important science stories of the day, free in your inbox. Nature medicine 18, 618623, doi: 10.1038/nm.2695 (2012). However, they found the migrated PCs was very few and these may attribute to: 1) the recipient are heathy rat. One example is using ultrasound-navigation for puncture. Cell and tissue research 347, 419427, doi: 10.1007/s00441-011-1306-3 (2012). The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. (C) Percentage of body weight changes over time. Normal mouse IgG was used as a substitute for the primary antibody as negative control. 4C). Summers, R. W. Novel and future medical management of inflammatory bowel disease. Small animals: 1 mL per 10 lb of body weight. Surg Clin North Am 87, 727741, doi: 10.1016/j.suc.2007.03.004 (2007). Srivastava, A. K. & Bulte, J. W. Seeing stem cells at work in vivo. some potent chemo and radio-labeled drugs)59. 2A), which guarantee the less interference from the background signal that coming from free dye. Admittedly, there may be an overlook of MSCs existence due to the tissue selection of frozen section and sensitivity of fluorescence imaging, the therapeutic differentiation of MSCs in our study were not clearly observed. From whole-body disease recovery, the amount of MSCs colons engraftment, tissue histological evaluation as well as levels of cytokines and TSG-6. [7] In 1969, errors depending on a variety of techniques of administering IP injections were analyzed, and a 12% error in placement was found when using a one-man procedure versus a 1.2% error when using a two-man procedure. Though IP injection showed benefits in many human and animal . Blood 113, 4657, doi: 10.1182/blood-2008-04-154138 (2009). The Journal of infectious diseases 198, 456464, doi: 10.1086/590112 (2008). DiR labeling showed no harm to the MSCs viability13 (Supplementary Figure S3). To compare the Ki-67 expression (one of the markers of cell proliferation) among the groups, the colon tissues were collected on day 7 (Fig. J Vis Exp, doi: 10.3791/1488 (2010). (A) The colonic mRNA expression of TNF- and IL-10 was analyzed by RT-PCR; (B) cytokine contents in colonic protein extracts were determined by ELISA; n=6 mice/group; n=3 for the control group (C) Serum TSG-6 level in different groups measured by ELISA. Transplantation proceedings 39, 573576, doi: 10.1016/j.transproceed.2006.12.019 (2007). Kalchenko, V. et al. 3; Supplementary Figure S6). . PubMed Another example of how intraperitoneal injections are used in studies involving rodents is the use of IP for micro-CT contrast enhanced detection of liver tumors. Female nude mice (Envigo) were anesthetized by intraperitoneal (IP) injection of ketamine/xylazine and immobilized in a stereotactic frame (Stoelting). Zhang, B. et al. Sci Rep 5, 16760, doi: 10.1038/srep16760 (2015). Schrepfer, S. et al. IP injections were suitable for serial imaging as well as imaging mice at multiple time points, which would be ideal for longitudinal drug treatment experiments. Mice are usu In study by Pennesi et al., MSCs was found to be able to prevent damages caused by collagen-induced arthritis, despite of lack of a detectable presence in the arthritic joint45. Gastric cancer is one of the most common malignant diseases worldwide [].Peritoneal dissemination is a characteristic feature of gastric cancer and is a critical factor underlying its poor prognosis [2-4].While clinical outcomes for gastric cancer patients with peritoneal dissemination have improved with advances in systemic and/or intraperitoneal (i.p) chemotherapy, desirable outcomes . . Select search scope, currently: articles+ all catalog, articles, website, & more in one search; catalog books, media & more in the Stanford Libraries' collections; articles+ journal articles & other e-resources However, the therapeutic impacts of cell delivery route that is critical for clinical translation are currently poorly understood. There are few examples of the use of intraperitoneal injections in humans cited in literature because it is mainly used to study the effects of drugs in mice. We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are "retired" from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. DiR-labeled cells were injected into DSS mice by three different ways. Condition. New chapters on interventional . Gastroenterology 149, 163176 e120, doi: 10.1053/j.gastro.2015.03.013 (2015). Blood and marrow stem cell transplants in autoimmune disease. 2020 May 9;12(5):439. doi: 10.3390/pharmaceutics12050439. There are increasing evidences showed that MSCs mediate their immunomodulatory effects through the induction of regulatory T cells (Treg cells)14. Skin application of non-rodents (miniature pigs) Epub 2020 Mar 18. Rodent (large / mouse) oral (intragastric), intravascular administration (tail vein injection, intraperitoneal injection, intramuscular injection and subcutaneous injection) Intragastric administration and oral taking of non-rodent (dog / monkey) solution and intravenous injection of extremities. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. It also shows how easily substances are absorbed through the peritoneal cavity after an IP injection. Choi, H., Lee, R. H., Bazhanov, N., Oh, J. Y. However, is IV injection the best way for MSCs delivery in IBD? Google Scholar. Total RNA was extracted with the RNAeasy Plus kit (QIAGEN). CBSKL2015Z01 and CBSKL2015Z12), PLA 12th Five-Year Program (BSW11J013) and National Science and Technology Major Project (No. 81371615), the Stake Key Laboratory Open Program of China (No. Other gap junction blockers were also occasionally reported to . Method. Disclaimer. One study attempted to diagnose hepatic hydrothorax with the use of injecting Sonazoid intraperitoneally. (A,B) Representative colon images and quantification of colon length; (C) myeloperoxidase (MPO) activity in colonic protein extracts; (D,E) Representative H&E staining and corresponding severity score; (F,G) Representative sirius red staining and quantification of collagen deposition. On the contrary, the anti-inflammatory IL-10 level were substantially elevated in IP group compared with the IV group and DSS control, but the inter-group difference between IP and AI group, AI and IV group were not identified. In our study, we also identify MSCs existence in nearby MLN. Intraperitoneal injection of 0.5-14.6 mg/kg 17- or 37-nm gold to mice produced an increase of brain dopamine, . Opioids can produce peripheral analgesic effects by activation of opioid receptors on sensory nerves. Distribution of GFP+ MSCs in colon 1 day after injection. Colonic mRNA expression of inflammatory mediators such as TNF-, IL-6, IL-1, IL-10 and IFN- were analyzed by real time-PCR in order to evaluate the local inflammatory environment (Fig). ", "Intraperitoneal injection (IP), Intravenous injection (IV) or anal injection (AI)? Mice were maintained in a light/temperature-controlled room and allowed to freely access to chow diet and water. The Scheme (Fig. Am J Gastroenterol 105, 289297, doi: 10.1038/ajg.2009.579 (2010). Antunes, M. A. et al. More recently the IP route has been used for chemotherapy in patients with intra-abdominal malignancies, i.e. These cells were confirmed as bone marrow MSCs using flow-cytometric analysis and differential identification (Supplementary Figures S1 and S2). Since the IP injection induced more cells migration to the inflamed colon, we further compared the difference in mucosa healing of different delivery routes. In this study, we compared therapeutic efficacy of three MSCs administration routes in DSS-induced colitis. GAPDH mRNA was used as an internal control to normalize mRNA expression. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/, Wang, M., Liang, C., Hu, H. et al. B.X. Given the range of potential doses, aiming for an injection volume of 5 l g -1 is advisable. Gynecol Oncol 81, 7781, doi: 10.1006/gyno.2000.6108 (2001). Twenty-five Kunming mice were exposed to Fe 3 O 4-nanoparticles via intraperitoneal injection daily for 1 week at doses of 0, 5, 10, 20, and 40 mg/kg. Stem cells international 2013, 732742, doi: 10.1155/2013/732742 (2013). Stem cells and development 21, 21892203, doi: 10.1089/scd.2011.0674 (2012). All the tissue sections in this study were scan and analyzed with Virtual slide scanning system (VS120-S, Olympus). The study overall defines appropriate doses and toxicity levels of dl1520 when injected intraperitoneally. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. [2] Intraperitoneal injections can be similar to oral administration in that hepatic metabolism could occur in both. Haematologica 93, 14571465, doi: 10.3324/haematol.12553 (2008). International journal of molecular medicine 37, 115125, doi: 10.3892/ijmm.2015.2413 (2016). Stem cells (Dayton, Ohio) 24, 386398, doi: 10.1634/stemcells.2005-0008 (2006). These complications include catheter infection, physical damages to intra-abdominal structures, such as vaginal vault perforation, bladder erosion and bowel perforation58 and direct drug toxicity to non-specific abdomen organ (e.g. and S.J. injection, or EBI) remains the most humane method available. & Dittel, B. N. Isolation of mouse peritoneal cavity cells. A., Ong, J. F. & Karp, J. M. Mesenchymal stem cells: immune evasive, not immune privileged. Sirius red staining showed disorganized collagen fibers in DSS control colon, which were diffusely distributed in the injured colon wall. MSCs has been well characterized of producing a range of modulatory cytokine, which inspires the designation of these cells as injury drugstore44. This case is a good example of how IP injections can be used to deliver a drug that can help to treat or cure a medical diagnosis over the use of other routes of delivery. PubMed Cancer cell 23, 107120, doi: 10.1016/j.ccr.2012.11.013 (2013). Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity). Ahmadian Kia, N. et al. and transmitted securely. Kushnir, C. L., Fleury, A. C., Silver, D. F. & Spirtos, N. M. Intraperitoneal Catheter Placement: The Hammock Technique. Rodents. Peri/postnatal development in rats was impaired with reduced pup weights, increased stillbirths, and increased pup mortality concurrent with maternal toxicity after intraperitoneal administration of tazobactam alone at doses 320 mg/kg/day (2 times the human dose based on body surface area) or of the combination piperacillin and tazobactam at . In contrast, GFP+ cells were showed in the lumen for AI group and lamina propria for IV group (Fig. Best way for mesenchymal stem cells transplantation for colitis. However, doubts exist over the use of Fe 3 O 4-nanoparticles in human beings. Interestingly, in some IP injection mice, GFP+ cells were observed in the epithelium of the inflamed colon. Injection into egg 1 month 20 doses 1 dose 1 month 1 month Once 3.0 mL/kg 5 mL/kg 10 mL/kg 2.5 mL/kg 1 mL/kg O.^L/g Well tolerated Well tolerated Well tolerated Well tolerated Well tolerated Less mortality 1 \Jg Increase in mortality, decreased activity during righting reflex, running time, visual discrimination, and olfactory aversion test Subcutaneous. Stem cells and development 18, 683692, doi: 10.1089/scd.2008.0253 (2009). The labeled cells were twice with warm fresh medium at 1500rpm for 5min to ensure complete removal of any unbound dye. 2010 May;27(5):735-8. doi: 10.1007/s11095-009-0031-z. Of the time points we tested (6, 16, 24 h) our results showed that a 16-h post-intraperitoneal injection image scan provided the best contrast in mice regardless of age or disease burden. 2019 Jun 24;36(9):126. doi: 10.1007/s11095-019-2646-z. PubMed Central Factors such as peritoneal inflammation, surface area, peritoneal blood flow, time of contact, etc, influence the drug transfer. The AI groups exhibited 9.5% and IV group showed 6.7% FoxP3+ cells, respectively (Fig. IP, intraperitoneal injection; IV, intravenous injection; AI anal injection; n = 6-8 for treatment group, n = 3 for DSS control. (A) Scheme of the treatment, the day of MSCs injection was defined as day 0. Key points to note. Infiltration (I): 0, no infiltrate; 1, infiltrate around crypt basis; 2, infiltrate reaching to lamina muscularis mucosa layer; 3, extensive infiltration reaching the muscularis mucosa with abundant edema; 4, infiltration of the submucosa layer. Article Cell stem cell 4, 206216, doi: 10.1016/j.stem.2009.02.001 (2009). Kenny et al. Thank you for visiting nature.com. We also evaluated serum TSG-6 in three MSCs administration route. Collagen deposition is another indicator for wound healing, however, extensive collagen deposition may hamper the gut reconstitution14. But how these miracle cells reach to the lumen and by which possible migration route? In order to compare the difference of MSCs colonization among the three delivery routes, a nontoxic NIR tracer DiR was introduced to label MSCs. completed the main experiment and wrote the first draft of the paper. Cells (human GBM-derived stem cells, GBM-8) 46 were cultured in Neurobasal medium supplemented with heparin, B27, . Li, Y. P. et al. Here, we combined the iDISCO + method and Fos immunostaining to confirm that the middle part of the right-side, but not the left-side, insular cortex in adult male mice is activated by intraperitoneal injection of lithium chloride. Near-infrared imaging and quantification of MSCs transplants. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Quantitative data are presented as the meanSD. Drug Deliv. 6B). Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. In most experimental studies, the MSCs treatment usually require at least 1106 cells/mouse, more frequently, a dose as high as 5106 cells/mouse to observe any effect12. Lu, Z., Wang, J., Wientjes, M. G. & Au, J. L. Intraperitoneal therapy for peritoneal cancer. This work is licensed under a Creative Commons Attribution 4.0 International License. Intraperitoneally applied drug forms are supposed to be located in the peritoneal cavity. Peyrin-Biroulet, L., Loftus, E. V. Jr., Colombel, J. F. & Sandborn, W. J. and H.H. Human bronchial epithelial cells (BEAS-2B and 16HBE) were purchased from Shanghai Zhongqiao Xinzhou Biological Co., Ltd, and cultured in a complete medium supplemented with growth factors and .1% penicillin-streptomycin. At day 5, mice were randomized and injected with MSCs (1106, 200L in volume) by three delivery routes (IP, AI and IV). M.W., C.L. After intraperitoneal injections, 30% of the female mice died, compared with 3% of the male. Monitor chest movements to make sure the animal is doing ok. On the mouse you want to make your IP injection in the lower right or left quadrant of abdomen trying to avoid hitting bladder, liver, or other internal organs. Journal of molecular neuroscience: MN 44, 178185, doi: 10.1007/s12031-010-9446-6 (2011). The authors declare no competing financial interests. Blonski, W., Buchner, A. M. & Lichtenstein, G. R. Treatment of ulcerative colitis. Use of lipophilic near-infrared dye in whole-body optical imaging of hematopoietic cell homing. 5C). During the observation, the body weight changes and fecal blood and their survival date was faithfully record. [citation needed], In humans, the method is widely used to administer chemotherapy drugs to treat some cancers, particularly ovarian cancer. Br J Rheumatol 36, 390392 (1997). In this study, the intraperitoneal injection was demonstrated as the superior way for MSCs administration in the setting of colitis amelioration. ISSN 2045-2322 (online). Pull back on the plunger to ensure negative pressure prior to injecting. Summary. Neutrophil infiltration was monitored by measuring MPO activity67. Parenteral administration routes include, but are not limited to epidermal, intraarterial, intramuscular (IM and depot IM) , intraperitoneal (IP) , intravenous (IV) , intrastemal injection or infusion techniques, intranasal (inhalation) , intrathecal, injection into the stomach, subcutaneous injections (subcutaneous (SQ and depot SQ . [2] Killing the rodent through an intraperitoneal route was originally recommended over other routes such as inhalants because it was thought to be more efficient and ethical. 2B). & Prockop, D. J. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Would you like email updates of new search results? Your peritoneal space. Cite this article. PubMed Central The problem is obvious, the solution is not: numbers do matter in cardiac cell therapy! One article reviews the injection of sodium pentobarbital to euthanize rodents intraperitoneally. 3) and the IV group preserved fewer cell number. The good cell-cell cross talk between MSCs and immune cells may be another contributor for better therapeutic effects. 4F,G). In humans respiratory side-effects were reported in five subjects taking mefloquine, but these cases constituted only 0.1% of studied population (Lobel et al., 2001). In view of these observations, and the fact that NASH is a PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: In Vitro and In Ovo Assessment. In colonic MLNs, similar results were observed, the MSCs administration induced more FoxP3+ cells accumulation than the control, but the inter-group differences were not evident (Supplementary Figure S8). Two early reports aroused the global interests of stem cell transplantation in IBD management. From the overall appearance, the hyperemia and edema of the colon in all MSCs treatment groups became milder than the DSS control. The results of this IP injection were the disappearance of the ascites associated with the rupture. Many published studies have showed the benefits of IV delivery in IBD treatment. 7B). Kean, T. J., Lin, P., Caplan, A. I. Changing Crohns disease management: need for new goals and indices to prevent disability and improve quality of life. Intra-abdominal adhesions can be a considerable source of morbidity and mortality. Drug delivery systems for intraperitoneal therapy. Mouse insulin gradually decreased and was no more detectable 13 weeks after STZ injection. Injections, also known as shots, deliver liquid medications, fluids, or nutrients directly into a person's body. Wang, N. et al. In general, it is preferred when large amounts of blood replacement fluids are needed or when low blood pressure or other problems prevent the use of a suitable blood vessel for intravenous injection. The need of intestinal resection in CD has remained stable8 and the colectomy rates in UC were still for 20% and 30% within 10 and 25 years of diseases duration9. Generally, MSCs treatments tend to decrease the pro-inflammatory cytokine (TNF-, IL-6, IL-1b and IFN-) and increase the anti-inflammatory cytokine (IL-10). Before Effects of different mesenchymal stromal cell sources and delivery routes in experimental emphysema. The AI and IV showed no significant intergroup difference, though AI had lower score (Fig. The fecal occult blood test on the day 3 also showed nearly complete absence of occult blood in IP group (Figure 1D). Intraperitoneal foreign bodies such as suture material, clips, and mesh also contribute to adhesion formation. Article Cells, tissues, organs 169, 1220 (2001). Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-alpha stimulated gene/protein 6.
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