Publications by year
2023
Gribben C, Lambert C, Messal HA, Hubber E-L, Rackham C, Evans I, Heimberg H, Jones P, Sancho R, Behrens A, et al (2023). Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.
Cell Stem Cell,
30(4), 498-499.
Author URL.
Hong T-W, Caxaria S, Daniels Gatward LF, Hussain S, Zhao M, King AJF, Rackham CL, Jones PM (2023). Mesenchymal stromal cell secretory molecules improve the functional survival of human islets.
Diabet MedAbstract:
Mesenchymal stromal cell secretory molecules improve the functional survival of human islets.
AIMS: Human islet transplantation as a therapy for type 1 diabetes is compromised by the loss of functional beta cells in the immediate post-transplantation period. Mesenchymal stromal cells (MSCs) and MSC-derived secretory peptides improve the outcomes of islet transplantation in rodent models of diabetes. Here we utilized a mouse model for human islet transplantation and assessed the effects of a cocktail of MSC-secreted peptides (screened by MSC-secretome for human islet GPCRs) on the functional survival of human islets. METHODS: Human islets from 9 donors (Age: 36-57; BMI: 20-35) were treated with a cocktail of human recombinant annexin A1 (ANXA1), stromal cell-derived factor-1 (SDF-1/CXCL12) and complement component C3 (C3a). Glucose stimulated insulin secretion (GSIS) was assessed in static incubation and cytokine-induced apoptosis was assessed by measuring caspase 3/7 activity. mRNA expression levels were determined by qPCR. Human islet function in vivo was assessed using a novel model for human islet transplantation into a T1D mouse model. Human islet function in vivo was assessed using islet transplantation under the kidney capsule of immunodeficient mice prior to STZ destruction of endogenous mouse beta cells to model T1DM. RESULTS: Pre-treatment with a cocktail of MSC-secreted peptides increased GSIS in vitro and protected against cytokine-induced apoptosis in human islets isolated from nine donors. Animals transplanted with either treated or untreated human islets remained normoglycemic for up to 28 days after STZ-administration to ablate the endogenous mouse beta cells, whereas non-transplanted animals showed significantly increased blood glucose immediately after STZ administration. Removal of the human islet graft by nephrectomy resulted in rapid increases in blood glucose to similar levels as the non-transplanted controls. Pre-treating human islets with the MSC-derived cocktail significantly improved glucose tolerance in graft recipients, consistent with enhanced functional survival of the treated islets in vivo. CONCLUSION: Pre-treating human islets before transplantation with a defined cocktail of MSC-derived molecules could be employed to improve the quality of human islets for transplantation therapy for type 1 diabetes.
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2021
Gribben C, Lambert C, Messal HA, Hubber E-L, Rackham C, Evans I, Heimberg H, Jones P, Sancho R, Behrens A, et al (2021). Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.
Cell Stem Cell,
28(11), 2000-2008.e4.
Abstract:
Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas.
Ductal cells have been proposed as a source of adult β cell neogenesis, but this has remained controversial. By combining lineage tracing, 3D imaging, and single-cell RNA sequencing (scRNA-seq) approaches, we show that ductal cells contribute to the β cell population over time. Lineage tracing using the Neurogenin3 (Ngn3)-CreERT line identified ductal cells expressing the endocrine master transcription factor Ngn3 that were positive for the δ cell marker somatostatin and occasionally co-expressed insulin. The number of hormone-expressing ductal cells was increased in Akita+/- diabetic mice, and ngn3 heterozygosity accelerated diabetes onset. scRNA-seq of Ngn3 lineage-traced islet cells indicated that duct-derived somatostatin-expressing cells, some of which retained expression of ductal markers, gave rise to β cells. This study identified Ngn3-expressing ductal cells as a source of adult β cell neogenesis in homeostasis and diabetes, suggesting that this mechanism, in addition to β cell proliferation, maintains the adult islet β cell population.
Abstract.
Author URL.
Hubber EL, Rackham CL, Jones PM (2021). Protecting islet functional viability using mesenchymal stromal cells.
Stem Cells Transl Med,
10(5), 674-680.
Abstract:
Protecting islet functional viability using mesenchymal stromal cells.
Islet transplantation is an emerging treatment for type 1 diabetes which offers the prospect of physiological control of blood glucose and reductions in acute hypoglycaemic episodes. However, current protocols are limited by a rapid decline in islet functional viability during the isolation process, culture period, and post-transplantation. Much of this can be attributed to the deleterious effects of hypoxic and cytokine stressors on β cells. One experimental strategy to improve the functional viability of islets is coculture or cotransplantation with mesenchymal stromal cells (MSCs). Numerous studies have shown that MSCs have the capacity to improve islet survival and insulin secretory function, and the mechanisms of these effects are becoming increasingly well understood. In this review, we will focus on recent studies demonstrating the capacity for MSCs to protect islets from hypoxia- and cytokine-induced stress. Islets exposed to acute hypoxia (1%-2% O2 ) or to inflammatory cytokines (including IFN-γ, TNF-α, and IL-B) in vitro undergo apoptosis and a rapid decline in glucose-stimulated insulin secretion. Coculture of islets with MSCs, or with MSC-conditioned medium, protects from these deleterious effects, primarily with secreted factors. These protective effects are distinct from the immunomodulatory and structural support MSCs provide when cotransplanted with islets. Recent studies suggest that MSCs may support secretory function by the physical transfer of functional mitochondria, particularly to metabolically compromised β cells. Understanding how MSCs respond to stressed islets will facilitate the development of MSC secretome based, cell-free approaches to supporting islet graft function during transplantation by protecting or repairing β cells.
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2020
King AJF, Rackham CL (2020). Assessing islet transplantation outcome in mice. In (Ed)
Methods in Molecular Biology, 265-280.
Abstract:
Assessing islet transplantation outcome in mice
Abstract.
Hubber EL, Rackham C, Pullen TJ, Jones PM (2020). Mesenchymal stromal cell induced gene expression changes in pancreatic islets.
Author URL.
Rackham CL, Hubber EL, Czajka A, Malik AN, King AJF, Jones PM (2020). Optimizing beta cell function through mesenchymal stromal cell-mediated mitochondria transfer.
STEM CELLS,
38(4), 574-584.
Author URL.
2019
Arzouni AA, Vargas-Seymour A, Dhadda PK, Rackham CL, Huang G-C, Choudhary P, King AJF, Jones PM (2019). Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function.
STEM CELLS TRANSLATIONAL MEDICINE,
8(9), 935-944.
Author URL.
Hubber E, Rackham C, Pullen T, Jones P (2019). Investigating mesenchymal stromal cell mediated support of islets after exposure to transplantation related stressors. Endocrine Abstracts
Rackham CL, Hubber EL, Malik AN, Choudhary P, King AJF, Jones PM (2019). Optimising islet transplantation efficiency through mesenchymal stromal cell mediated mitochondrial transfer.
Author URL.
Rackham C, Hubber E, Czajka A, Malik A, Choudhary P, King A, Jones P (2019). Optimising transplantation efficiency through mesenchymal stromal cell modulated improvements in islet mitochondrial bioenergetics.
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2018
Rackham CL, Dhadda PK, Simpson SJS, Godazgar M, King AJF, Jones PM (2018). Composite mesenchymal stromal cell islets: Implications for transplantation via the clinically preferred intraportal route. Transplantation Direct, 4(4).
Rackham CL, Amisten S, Persaud SJ, King AJF, Jones PM (2018). Harnessing the mesenchymal stromal cell secretome to improve the efficiency of islet transplantation.
Author URL.
Rackham CL, Amisten S, Persaud SJ, King AJF, Jones PM (2018). Mesenchymal stromal cell secretory factors induce sustained improvements in islet function pre- and post-transplantation.
CYTOTHERAPY,
20(12), 1427-1436.
Author URL.
Rackham CL, Jones PM (2018). Potential of mesenchymal stromal cells for improving islet transplantation outcomes.
CURRENT OPINION IN PHARMACOLOGY,
43, 34-39.
Author URL.
2017
Vargas AE, Arzouni AA, Dhadda PK, Huang GC, Choudhary P, King AJF, Rackham CL, Jones PM (2017). Beneficial effects of human mesenchymal stromal cells on human islet function via annexin A1 secretion.
Author URL.
Malik AN, Czajka A, Thubron EB, Rackham CL, Austin ALF, King A (2017). Diabetes induced changes in circulating and kidney mitochondrial DNA: a potential novel pathway of renal damage.
Author URL.
Arzouni AA, Vargas-Seymour A, Rackham CL, Dhadda P, Huang G-C, Choudhary P, Nardi N, King AJF, Jones PM (2017). Mesenchymal stromal cells improve human islet function through released products and extracellular matrix.
CLINICAL SCIENCE,
131(23), 2835-2845.
Author URL.
Rackham C, Czajka A, Malik A, Huthoff H, King A, Jones P (2017). Mitochondria to the rescue: a novel Mesenchymal Stromal Cell-mediated mechanism of enhanced islet function.
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2016
Rackham CL, Vargas AE, Hawkes RG, Amisten S, Persaud SJ, Austin ALF, King AJF, Jones PM (2016). Annexin A1 is a Key Modulator of Mesenchymal Stromal Cell-Mediated Improvements in Islet Function.
DIABETES,
65(1), 129-139.
Author URL.
2015
Rackham CL, Dhadda PK, Hawkes RG, Amisten SB, Persaud SJ, Liu B, King AJF, Jones PM (2015). Mesenchymal stromal cells improve islet insulin secretory function via annexin A1 production.
Author URL.
Moreau A, Blair PA, Chai J-G, Ratnasothy K, Stolarczyk E, Alhabbab R, Rackham CL, Jones PM, Smyth L, Elgueta R, et al (2015). Transitional-2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival.
EUROPEAN JOURNAL OF IMMUNOLOGY,
45(3), 843-853.
Author URL.
2014
Rackham CL, Dhadda PK, King AJF, Jones PM (2014). Pre-culturing islets with adipose-derived mesenchymal stem cells represents an effective strategy for improving transplantation efficiency at the clinically preferred intraportal site.
Author URL.
Rackham CL, Dhadda PK, Le Lay AM, King AJF, Jones PM (2014). Preculturing Islets with Adipose-Derived Mesenchymal Stromal Cells is an Effective Strategy for Improving Transplantation Efficiency at the Clinically Preferred Intraportal Site.
Cell Med,
7(1), 37-47.
Abstract:
Preculturing Islets with Adipose-Derived Mesenchymal Stromal Cells is an Effective Strategy for Improving Transplantation Efficiency at the Clinically Preferred Intraportal Site.
We have recently shown that preculturing islets with kidney-derived mesenchymal stromal cells (MSCs) improves transplantation outcome in streptozotocin-diabetic mice implanted with a minimal mass of islets beneath the kidney capsule. In the present study, we have extended our previous observations to investigate whether preculturing islets with MSCs can also be used to enhance islet function at the clinically used intraportal site. We have used MSCs derived from adipose tissue, which are more readily accessible than alternative sources in human subjects and can be expanded to clinically efficacious numbers, to preculture islets throughout this study. The in vivo efficacy of grafts consisting of islets precultured alone or with MSCs was tested using a syngeneic streptozotocin-diabetic minimal islet mass model at the clinically relevant intraportal site. Blood glucose concentrations were monitored for 1 month. The vascularization of islets precultured alone or with MSCs was investigated both in vitro and in vivo, using immunohistochemistry. Islet insulin content was measured by radioimmunoassay. The effect of preculturing islets with MSCs on islet function in vitro was investigated using static incubation assays. There was no beneficial angiogenic influence of MSC preculture, as demonstrated by the comparable vascularization of islets precultured alone or with MSCs, both in vitro after 3 days and in vivo 1 month after islet transplantation. However, the in vitro insulin secretory capacity of MSC precultured islets was superior to that of islets precultured alone. In vivo, this was associated with improved glycemia at 7, 14, 21, and 28 days posttransplantation, in recipients of MSC precultured islets compared to islets precultured alone. The area of individual islets within the graft-bearing liver was significantly higher in recipients of MSC precultured islets compared to islets precultured alone. Our experimental studies suggest that preculturing islets with MSCs represents a favorable strategy for improving the efficiency of clinical islet transplantation.
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Author URL.
Dhadda PK, Rackham C, Le Lay A, Kerby A, Huang GC, Jones P (2014). The effects of three human mesenchymal stromal cell populations upon human islet function in vitro.
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2013
King A, Rackham C (2013). Co-transplantation of islets with mesenychymal stem cells improves islet revascularization and reversal of hyperglycemia. In (Ed)
Stem Cells and Cancer Stem Cells, Volume 10: Therapeutic Applications in Disease and Injury, 271-282.
Abstract:
Co-transplantation of islets with mesenychymal stem cells improves islet revascularization and reversal of hyperglycemia
Abstract.
Rackham CL, Jones PM, King AJ (2013). Maintaining islet morphology is beneficial for transplantation outcome in diabetic mice.
Author URL.
Rackham CL, Jones PM, King AJF (2013). Maintenance of Islet Morphology is Beneficial for Transplantation Outcome in Diabetic Mice.
PLOS ONE,
8(2).
Author URL.
Rackham CL, Dhadda PK, Chagastelles PC, Simpson SJS, Dattani AA, Bowe JE, Jones PM, King AJF (2013). Pre-culturing islets with mesenchymal stromal cells using a direct contact configuration is beneficial for transplantation outcome in diabetic mice.
CYTOTHERAPY,
15(4), 449-459.
Author URL.
Dhadda P, Rackham C, Le Lay A, Kerby A, Huang G-C, Jones P (2013). Preculture of Human Islets with Mesenchymal Stem Cells in a Direct Contact Configuration Enhances Islet Function in Vitro.
Author URL.
Rackham C, Dhadda P, Le Lay A, Kerby A, Jones P, King A (2013). Strategies to Improve Intraportal Islet Transplantation Outcome in Mice Using Mesenchymal Stem Cells.
Author URL.
2012
Kerby A, Rackham CL, Chagastelles PC, King AJF (2012). Co-Encapsulation of Islets with Mesenchymal Stem Cells Improves Islet Function.
Author URL.
Dhadda PK, Rackham CL, Simpson SJS, Jones PM (2012). Co-culture of islets with mesenchymal stem cells in direct contact configurations improves islet function in vitro.
Author URL.
Rackham CL, Dhadda PK, Datttani AA, Bowe JE, Jones PM, King AJF (2012). Preculture of islets with mesenchymal stem cells enhances islet function in vitro and produces superior transplantation outcome in diabetic mice.
Author URL.
2011
Mucha N, Clarkin C, Rackham C, King A, Wheeler-Jones C, Jones P (2011). A potential role for EphB:Ephrin B expression in the regulation of beta cell and islet endothelial cell communication. Diabetologie und Stoffwechsel, 6(04).
Rackham CL, Chagastelles PC, Nardi NB, Hauge-Evans AC, Jones PM, King AJF (2011). Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice.
DIABETOLOGIA,
54(5), 1127-1135.
Author URL.
2010
King AJF, Rackham C, Chagastelles P, Jones PM (2010). Co-transplantation with mesenchymal stem cells improves islet transplantation outcome in mice.
Author URL.
2009
Skowera A, Ellis RJ, Varela-Calvino R, Arif S, Huang GC, Van-Krinks C, Zaremba A, Rackham C, Allen JS, Tree TIM, et al (2009). CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope (vol 118, pg 3390, 2008).
JOURNAL OF CLINICAL INVESTIGATION,
119(9), 2843-2843.
Author URL.
Skowera A, Ellis RJ, Varela-Calviño R, Arif S, Huang GC, Van-Krinks C, Zaremba A, Rackham C, Allen JS, Tree TIM, et al (2009). Inherited human cPLA2α deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction. Journal of Clinical Investigation, 119(9), 2844-2844.
Allen JS, Pang K, Skowera A, Ellis R, Rackham C, Lozanoska-Ochser B, Tree T, Leslie RDG, Tremble JM, Dayan CM, et al (2009). Plasmacytoid Dendritic Cells Are Proportionally Expanded at Diagnosis of Type 1 Diabetes and Enhance Islet Autoantigen Presentation to T-Cells Through Immune Complex Capture.
DIABETES,
58(1), 138-145.
Author URL.
2008
Skowera A, Ellis RJ, Varela-Calvino R, Arif S, Huang GC, Van-Krinks C, Zaremba A, Rackham C, Allen JS, Tree TIM, et al (2008). CTLs are targeted to kill beta cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope.
JOURNAL OF CLINICAL INVESTIGATION,
118(10), 3390-3402.
Author URL.
