Cell Loss in Isolated Human Islets Occurs by Apoptosis

Paraskevas, Steven; Maysinger, Dusica; Wang, Rennien; Duguid, William P; Rosenberg, Lawrence

doi:10.1097/00006676-200004000-00008

Cited by 229Pancreatic function and diabetesCell death mechanisms and regulationDiabetes and associated disorders

Cell Loss in Isolated Human Islets Occurs by Apoptosis

Paraskevas, Steven, Maysinger, Dusica, Wang, Rennien, Duguid, William P, Rosenberg, Lawrence·2000·Pancreas

DOI 10.1097/00006676-200004000-00008

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Abstract

Purified islet allografts have largely failed to maintain long-term glucose homeostasis in human recipients, and the reasons for this are unclear. It is noteworthy, however, that islet isolation destroys or removes cellular and noncellular elements of the pancreas that could play an important role in supporting islet survival. The purpose of this study was to determine whether human islet isolation leads to the induction of programmed cell death. Human islets were enzymatically isolated from cadaveric donor pancreata using Liberase or Collagenase P, purified over a discontinuous BSA gradient, then cultured in RPMI 1640 at 37 degrees C in 5% CO2 for < or = 7 days. Islets were examined daily by routine histology and immunocytochemistry for islet hormones, DNA fragmentation [cell death; enzyme-linked immunosorbent assay (ELISA) and TUNEL assay] and for transglutaminase (TG) activity, two indicators of apoptosis. TG activity and DNA fragmentation increased by 1,000% and 1,890%, respectively (p < 0.05) This corresponded to the appearance of pyknotic nuclei on light microscopy, the presence of apoptotic bodies on electron microscopy, and the demonstration of TUNEL-positive cells. These were present primarily in a distribution that corresponded to the insulin-immunoreactive cells. At 5 days, 31.4 +/- 2.2% of islet cells were TUNEL positive. In summary, apoptosis of islet cells appears soon after islet isolation, and involves primarily the beta cell. This is the first report of apopt…

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The stress of purification from the pancreas can damage islets before transplantation.
“Furthermore, the stress of purification from the pancreas can damage islets before transplantation.27”
From Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes (2023) · cites this paper as [27]

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Self-citation
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Background
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Background
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Self-citation
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Background
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Background
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Self-citation
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Upgrading Pretransplant Human Islet Culture Technology Requires Human Serum Combined With Media Renewal
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Background
Phosphatidylinositol 3-Kinase Signaling to Akt Mediates Survival in Isolated Canine Islets of Langerhans
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Self-citation
Simvastatin induces activation of the serine-threonine protein kinase AKT and increases survival of isolated human pancreatic islets
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Background
Assessment of β-Cell Mass and α- and β-Cell Survival and Function by Arginine Stimulation in Human Autologous Islet Recipients
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“Apoptosis is a primary mechanism for loss of function in b cells, and can be initiated at the time of tissue procurement, islet isolation or transplantation (16).”
Background
Allogeneic bone marrow supports human islet beta cell survival and function over six months.
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Background
Autocrine insulin action activates Akt and increases survival of isolated human islets
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BackgroundSelf-citation
Flexible Management of Enzymatic Digestion Improves Human Islet Isolation Outcome from Sub‐Optimal Donor Pancreata
Balamurugan, A. N., Chang, Y., Fung, J. J., Trucco, M., & Bottino, R. (2003) · American Journal of Transplantation · doi:10.1046/j.1600-6143.2003.00184.x · Cited by 48 · see citing works
“Studies have also demonstrated that destruction of the extracellular matrix during enzymatic digestion of the pancreas leads to islet cell apoptosis (11).”
Background
Pancreatic islet transplantation in the treatment of diabetes mellitus.
Shapiro, A. M. J., Ryan, E., & Lakey, J. (2001) · Best practice & research. Clinical endocrinology & metabolism · doi:10.1053/beem.2001.0138 · Cited by 51 · see citing works
Carnosine protects pancreatic beta cells and islets against oxidative stress damage.
Miceli, V., Pampalone, M., Frazziano, G., Grasso, G., Rizzarelli, E., Ricordi, C., Casu, A., Iannolo, G., & Conaldi, P. (2018) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.02.016 · Cited by 50 · see citing works
Prediction of Marginal Mass Required for Successful Islet Transplantation
Papas, K., Colton, C., Qipo, A., Wu, H.-Y., Nelson, R., Hering, B., Weir, G., & Koulmanda, M. (2010) · Journal of investigative surgery · doi:10.3109/08941930903410825 · Cited by 50 · see citing works
“Because pancreata are procured from brain dead donors [9–11], exposed to ischemia [12–14], and subjected to stressful mechanical and enzymatic procedures during isolation [4], organ donor characteristics alone do not necessarily predict isolated islet quality.”
Background
Effect of short‐term culture on functional and stress‐related parameters in isolated human islets
Ihm, S., Matsumoto, I., Zhang, H. J., Ansite, J., & Hering, B. (2009) · Transplant International · doi:10.1111/j.1432-2277.2008.00769.x · Cited by 49 · see citing works
Similar Islet Function in Islet Allotransplant and Autotransplant Recipients, Despite Lower Islet Mass in Autotransplants
Bellin, M., Sutherland, D., Beilman, G. J., Hong-McAtee, I., Balamurugan, A., Hering, B., & Moran, A. (2011) · Transplantation · doi:10.1097/tp.0b013e318203fd09 · Cited by 48
“First, the islet isolation process strips the islets of their native blood supply resulting in relative hypoxia, an upregulation of proapoptotic factors, and -cell apoptosis (9, 10, 24).”
Background
Limited extent and consequences of pancreatic SARS-CoV-2 infection
van der Heide, V., Jangra, S., Cohen, P., Rathnasinghe, R., Aslam, S., Aydillo, T., Geanon, D., Handler, D., Kelley, G., Lee, B., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110508 · Cited by 47 · see citing works
“Note that cumulative impact of human islet isolation, transport, culture and dissociation required for FC analyses is associated with considerable cell death (Maachi et al., 2021; Paraskevas et al., 2000).”
Immune Response to Extracellular Vesicles From Human Islets of Langerhans in Patients With Type 1 Diabetes
Rutman, A. K., Negi, S., Gasparrini, M., Hasilo, C. P., Tchervenkov, J., & Paraskevas, S. (2018) · Endocrinology · doi:10.1210/en.2018-00649 · Cited by 52 · see citing works
Self-citation
Regulated Cell Death Seen through the Lens of Islet Transplantation
Bruni, A. D. C., Bornstein, S. R., Linkermann, A., & Shapiro, A. M. J. (2018) · Cell Transplantation · doi:10.1177/0963689718766323 · Cited by 48 · see citing works
Alginate-based tissue-specific bioinks for multi-material 3D-bioprinting of pancreatic islets and blood vessels: A step towards vascularized pancreas grafts
Idaszek, J., Volpi, M., Paradiso, A., Quoc, M. N., Górecka, Ż., Klak, M., Tymicki, G., Berman, A., Wierzbicki, M., Jaworski, S., et al. (2021) · Bioprinting · doi:10.1016/j.bprint.2021.e00163 · Cited by 54 · see citing works
Ductal Injection of JNK Inhibitors Before Pancreas Preservation Prevents Islet Apoptosis and Improves Islet Graft Function
Noguchi, H., Matsumoto, S., Onaca, N., Naziruddin, B., Jackson, A., Ikemoto, T., Shimoda, M., Fujita, Y., Chujo, D., Iwanaga, Y., et al. (2008) · Human Gene Therapy · doi:10.1089/hum.2008.125 · Cited by 43
“However, successful transplantation is limited by the availability of human islets as well as by a high loss of islets during isolation (Paraskevas et al. , 2000) and after transplantation (Davalli et al. , 1996).”
Human islets and dendritic cells generate post‐translationally modified islet autoantigens
Mclaughlin, R. J., de Haan, A., Zaldumbide, A., de Koning, E. D., Ru, D. A. H., van Veelen, P. V., van Lummel, M., & Roep, B. (2016) · Clinical and Experimental Immunology · doi:10.1111/cei.12775 · Cited by 42
Intra‐Ductal Glutamine Administration Reduces Oxidative Injury During Human Pancreatic Islet Isolation
Ávila, J., Barbaro, B., Gangemi, A., Romagnoli, T., Kuechle, J., Hansen, M., Shapiro, J., Testa, G., SANKARY, H. N., Benedetti, E., et al. (2005) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2005.01109.x · Cited by 43 · see citing works
In situ type I oligomeric collagen macroencapsulation promotes islet longevity and function in vitro and in vivo.
Stephens, C. H., Orr, K. S., Acton, A. J., Tersey, S., Mirmira, R., Considine, R., & Voytik-Harbin, S. (2018) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00073.2018 · Cited by 41 · see citing works
“Upon islet isolation and conventional culture in suspension, insulin-producing cells undergo multiple cell death processes including apoptosis, anoikis, and necrosis, which has been attributed to the loss of critical cell-ECM interactions, biophysical cues, and vascularization (23, 44, 54, 70).”
Background
Evidence of Endoplasmic Reticulum Stress Mediating Cell Death in Transplanted Human Islets
Negi, S., Park, S. H., Jetha, A., Aikin, R. A., Tremblay, M. L., & Paraskevas, S. (2011) · Cell Transplantation · doi:10.3727/096368911x603639 · Cited by 39 · see citing works
Self-citation
Inhibition of caspase-mediated PARP-1 cleavage results in increased necrosis in isolated islets of Langerhans
Aikin, R., Rosenberg, L., Paraskevas, S., & Maysinger, D. (2004) · Journal of molecular medicine · doi:10.1007/s00109-004-0540-5 · Cited by 41 · see citing works
“... islet cell mass [2, 3]. Hence, multiple organ donors are often necessary to meet the requirements of a single patient [1, 4]. Additionally, the harshness of the isolation procedure exposes islets to significant stress, which could contribute to decreased viability following isolation [2, 5, 6]. We have previously…”
MethodSelf-citation
A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction
Bender, R. H. F., O’Donnell, B. T., Shergill, B. S., Pham, B. Q., Tahmouresie, S., Sanchez, C. N., Juat, D. J., Hatch, M. M. S., Shirure, V. S., Wortham, M., et al. (2023) · Biofabrication · doi:10.1088/1758-5090/ad17d0 · Cited by 42 · see citing works
“Standard islet isolation procedures physically disrupt and remove both blood vessels and ECM, causing structural damage, reduced glucose responsiveness, and death of a proportion of islets [19, 20].”
Background
Improved Islet Yields from Pancreas Preserved in Perflurocarbon Is Via Inhibition of Apoptosis Mediated by Mitochondrial Pathway
Ramachandran, S., Desai, N., Goers, T., Benshoff, N., Olack, B., Shenoy, S., Jendrisak, M., Chapman, W. C., & Mohanakumar, T. (2006) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2006.01368.x · Cited by 40 · see citing works
“This cell loss has been shown to be initiated shortly after islet isolation with detectable apoptosis within 48 h of isolation (16).”
Background
Pancreas preservation by the 2-layer cold storage method before islet isolation protects isolated islets against apoptosis through the mitochondrial pathway.
Matsuda, T., Suzuki, Y., Tanioka, Y., Toyama, H., Kakinoki, K., Hiraoka, K., Fujino, Y., & Kuroda, Y. (2003) · Surgery · doi:10.1067/s0039-6060(03)00165-x · Cited by 40 · see citing works
Pancreas and islet cell transplantation.
Bottino, R., Trucco, M., Balamurugan, A., & Starzl, T. (2002) · Best practice & research. Clinical gastroenterology · doi:10.1053/bega.2002.0318 · Cited by 40 · see citing works
Dominant negative mutant forms of the cAMP response element binding protein induce apoptosis and decrease the anti-apoptotic action of growth factors in human islets
Sarkar, S., Gunter, J., Bouchard, R. J., Reusch, J., Wiseman, A., Gill, R. G., Hutton, J., & Pugazhenthi, S. (2007) · Diabetologia · doi:10.1007/s00125-007-0707-z · Cited by 39 · see citing works
“Apoptosis is considered to be the major cause of islet loss as shown by the presence of several apoptotic markers [2, 3].”
Background
Pancreatic islet transplantation for treating diabetes
Matsumoto, S., Noguchi, H., Yonekawa, Y., Okitsu, T., Iwanaga, Y., Liu, X.-L., Nagata, H., Kobayashi, N., & Ricordi, C. (2006) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.6.1.23 · Cited by 39 · see citing works
“4 Antiapoptotic strategies It was shown that the islet isolation process induced apoptosis to isolated islets [130-133], and antiapoptotic reagents were shown to improve engraftment.”
Background
Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone
Schubert, U., Schmid, J., Lehmann, S., Zhang, X. Y., Morawietz, H., Block, N. L., Kanczkowski, W., Schally, A. V., Bornstein, S. R., & Ludwig, B. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221505110 · Cited by 36 · see citing works
“One major limitation of advancements in islet transplantation is the partial or total loss of the islet graft within a few days or weeks after its implantation (8).”
Background
Insulin-like growth factor II allows prolonged blood glucose normalization with a reduced islet cell mass transplantation.
Robitaille, R., Dusseault, J., Henley, N., Rosenberg, L., & Hallé, J. (2003) · Endocrinology · doi:10.1210/en.2002-0185 · Cited by 38
Self-citation
Total pancreatectomy and islet autotransplantion for chronic and recurrent acute pancreatitis
McEachron, K., & Bellin, M. (2018) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000458 · Cited by 37
Presence of diabetes autoantigens in extracellular vesicles derived from human islets
Hasilo, C., Negi, S., Allaeys, I., Cloutier, N., Rutman, A., Gasparrini, M., Bonneil, É., Thibault, P., Boilard, É., & Paraskevas, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-04977-y · Cited by 37 · see citing works
Self-citation
Unmethylated insulin DNA is elevated after total pancreatectomy with islet autotransplant: assessment of a novel beta cell marker
Bellin, M., Clark, P., Usmani-Brown, S., Dunn, T., Beilman, G. J., Chinnakotla, S., Pruett, T., Ptacek, P., Hering, B., Wang, Z., et al. (2016) · American Journal of Transplantation · doi:10.1111/ajt.14054 · Cited by 37
“The islet isolation procedure itself induces high rates of beta cell apoptosis (2,3).”
Background
Microfluidic perfusion systems for secretion fingerprint analysis of pancreatic islets: applications, challenges and opportunities.
Castiello, F. R., Heileman, K., & Tabrizian, M. (2016) · Lab on a Chip · doi:10.1039/c5lc01046b · Cited by 37 · see citing works
Three‐dimensional pancreas organogenesis models
Grapin‐Botton, A. (2016) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12720 · Cited by 36 · see citing works
Improving pancreatic islet in vitro functionality and transplantation efficiency by using heparin mimetic peptide nanofiber gels.
Uzunalli, G., Tumtas, Y., Delibaşı, T., Yasa, O., Mercan, S., Guler, M. O., & Tekinay, A. B. (2015) · Acta Biomaterialia · doi:10.1016/j.actbio.2015.04.032 · Cited by 35
“during isolation limit the success of islet transplantations [14,15].”
Background
The Role of the Alternative Complement Pathway in Early Graft Loss After Intraportal Porcine Islet Xenotransplantation
Kang, H. J., Lee, H., Ha, J., Lee, J.-I., Shin, J.-S., Kim, K.-Y., Park, J. Y., Kim, J.-S., Min, S., Park, C.-G., et al. (2014) · Transplantation · doi:10.1097/tp.0000000000000069 · Cited by 35
“Several factors, including the islet isolation process (8, 9), low oxygen tension in the transplanted islets (10), activation of innate immune cells, and immediate inflammatory responses (11, 12) termed instant blood-mediated inflammatory reaction (IBMIR), have been proposed to contribute to the early damage of islet…”
Background
Tumor Necrosis Factor- Production by Human Islets Leads to Postisolation Cell Death
Hanley, S., Liu, S.-Q., Lipsett, M., Castellarin, M., Rosenberg, L., Tchervenkov, J., & Paraskevas, S. (2006) · doi:10.1097/01.tp.0000234787.05789.23 · Cited by 35
Self-citation
Pancreatic Pseudoislets: An Organoid Archetype for Metabolism Research
Friedlander, M. S. H., Nguyen, V., Kim, S. K., & Bevacqua, R. J. (2021) · Diabetes · doi:10.2337/db20-1115 · Cited by 37 · see citing works
“In contrast to analyses of intact islets (52,53), three studies reported that pseudoislet function improved with extended culture (11,37,40).”
Result
Cell-Permeable Pentapeptide V5 Inhibits Apoptosis and Enhances Insulin Secretion, Allowing Experimental Single-Donor Islet Transplantation in Mice
Rivas-Carrillo, J., Soto-Gutierrez, A., Navarro-Alvarez, N., Noguchi, H., Okitsu, T., Chen, Y., Yuasa, T., Tanaka, K., Narushima, M., Miki, A., et al. (2007) · Diabetes · doi:10.2337/db06-1679 · Cited by 33 · see citing works
“Isolation of human islets is very stressful on the cells as it disrupts cell-cell and cell-matrix interactions and results in islet apoptosis (9,12,13,17, 32,38,39).”
Background
Combination strategy of multi-layered surface camouflage using hyperbranched polyethylene glycol and immunosuppressive drugs for the prevention of immune reactions against transplanted porcine islets
Haque, M. R., Jeong, J.-H., & Byun, Y. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.01.039 · Cited by 29 · see citing works
Advances and challenges of the cell-based therapies among diabetic patients
Raoufinia, R., Rahimi, H. R., Saburi, E., & Moghbeli, M. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05226-3 · Cited by 29 · see citing works
“Using multiple donors also increases rejection risk, while isolation of the islets can cause tissue damage [159].”
Background
The Impact of Oxidative Stress on Islet Transplantation and Monitoring the Graft Survival by Non-Invasive Imaging
Ramkumar, K. M., Sekar, T. V., Bhakkiyalakshmi, E., Foygel, K., Rajaguru, P., Berger, F., & Paulmurugan, R. (2013) · Current Medicinal Chemistry · doi:10.2174/0929867311320090003 · Cited by 27 · see citing works
Enriched Human Pancreatic Ductal Cultures Obtained from Selective Death of Acinar Cells Express Pancreatic and Duodenal Homeobox Gene-1 Age-Dependently
Street, C. N., Lakey, J. R. T., Rajotte, R. V., Shapiro, A. J., Kieffer, T. J., Lyon, J. G., Kin, T., & Korbutt, G. S. (2004) · The Review of Diabetic Studies · doi:10.1900/rds.2004.1.66 · Cited by 26 · see citing works
“Several studies have proposed that one reason for early islet graft failure post-transplant is due to apoptosis induced during isolation [29, 30], and methods have been suggested to decrease this cell death with varying results [31, 30].”
Result
Heat Shock Protein 27 Overexpression Mitigates Cytokine-Induced Islet Apoptosis and Streptozotocin-Induced Diabetes
Dai, T., Chamberlin, M. P., Natarajan, R. D., Todorov, I., Ma, J., LaPage, J. A., Phillips, L. M., Nast, C. C., Becerra, D., Chuang, P. Y., et al. (2009) · Endocrinology · doi:10.1210/en.2008-0732 · Cited by 29 · see citing works
Characterization of Islet Preparations
Colton, C. K., Papas, K. K., Pisania, A., Rappel, M. J., Powers, D. E., O’Neil, J. J., Omer, A., Weir, G. C., & Bonner‐Weir, S. (2007) · Elsevier eBooks · doi:10.1016/b978-012369415-7/50007-7 · Cited by 35 · see citing works
Circulating Unmethylated Insulin DNA As a Biomarker of Human Beta Cell Death: A Multi-laboratory Assay Comparison
Speake, C., Ylescupidez, A., Neiman, D., Shemer, R., Gläser, B., Tersey, S. A., Usmani‐Brown, S., Clark, P. L., Wilhelm, J. J., Bellin, M. D., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa008 · Cited by 30 · see citing works
A Nonhematopoietic Erythropoietin Analogue, ARA 290, Inhibits Macrophage Activation and Prevents Damage to Transplanted Islets
Watanabe, M., Lundgren, T., Saito, Y., Cerami, A., Brines, M., Östenson, C., & Kumagai-Braesch, M. (2016) · Transplantation · doi:10.1097/tp.0000000000001026 · Cited by 26 · see citing works
“The islet isolation process itself also triggers a cascade of stressful events in the islets involving apoptosis and the production of proinflammatory molecules that negatively influence islet function and produce detrimental effects after PITx.(3,4) Hence, an efficient strategy for preventing islet damage during the…”
Background

Authors: Paraskevas, S., Maysinger, D., Wang, R., Duguid, W. P., & Rosenberg, L.
Affiliations: Montreal General Hospital (CA)
Corresponding author: Rosenberg, Lawrence
ORCID: Paraskevas, Steven
Venue: Pancreas
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2000-04
Volume: 20
Issue: 3
Pages: 270-276
ISSN: 0885-3177 (ISSN-L)
DOI: 10.1097/00006676-200004000-00008
OpenAlex: W2046236577
Cited by: 229
References: 0
Citations by year: 2024: 6 · 2023: 7 · 2022: 6 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 15 · 2017: 10 · 2016: 11 · 2015: 9 · 2014: 7 · 2013: 14 · 2012: 12
FWCI: 7.56
Type: journal article
Language: en
Open access: closed
Locations: Pancreas (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords: islet isolation, apoptosis, beta-cell death, human pancreatic islets, islet transplantation, transglutaminase activity, DNA fragmentation, TUNEL, Liberase, islet purification
MeSH terms: Adolescent, Adult, Cadaver, Cell Separation, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Islets of Langerhans, Microscopy, Electron, Middle Aged, Transglutaminases, Thermolysin, Apoptosis, Collagenases, In Situ Nick-End Labeling, DNA Fragmentation

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Cell Loss in Isolated Human Islets Occurs by Apoptosis

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