Cell-Based Therapies for Canine Type 1 Diabetes

Conventional treatment of canine type 1 diabetes mellitus (T1DM) successfully manages clinical signs but does not restore the lost population of insulin-producing β-cells. This has driven the development of regenerative and cell-based therapies aimed at replacing the underlying endocrine dysfunction rather than simply supplementing insulin. Although these approaches are not yet part of routine veterinary practice, they represent an important area of progress that practicing veterinarians should understand as the field continues to evolve. 

From pancreatic islet transplantation to stem cell-derived β-cells and organoid technology, multiple strategies are being explored to achieve longer-lasting glycaemic control while reducing dependence on lifelong insulin administration. 

Replacing Lost β-Cells Through Islet Transplantation 

One of the earliest approaches focused on replacing functional pancreatic tissue through pancreatic or islet allotransplantation. Compared with whole-pancreas transplantation, islet transplantation offers a less invasive method of restoring insulin production while avoiding many of the surgical challenges associated with transplanting the entire pancreas¹. 

Several canine applications have demonstrated encouraging outcomes. Intrahepatic transplantation of pancreatic islets achieved normoglycaemia in dogs receiving immunosuppressive therapy, although graft rejection occurred after immunosuppression was withdrawn. Longer periods of normoglycaemia, ranging from 253 to 716 days, have also been reported following multi-donor intrahepatic islet transplantation with cyclosporin-A¹. 

To reduce dependence on immunosuppressive drugs, encapsulation technologies were developed to isolate transplanted islets from the recipient's immune system. Various encapsulated systems maintained normoglycaemia for periods ranging from one month to over one year, while other approaches reduced exogenous insulin requirements and improved plasma insulin concentrations¹. 

Despite these promising results, practical barriers remain. Donor pancreas availability, specialised infrastructure, technical expertise, good manufacturing practice (GMP) requirements, logistical complexity, ethical considerations, and overall cost continue to limit widespread clinical implementation^1,2,3. 

Stem Cells and Organoids: Building New Insulin-Producing Cells 

Rather than relying on donor pancreases, regenerative medicine aims to generate new insulin-producing cells in vitro. 

Three stem cell sources have been considered for this purpose: 

• Embryonic stem cells (ESCs) 

• Induced pluripotent stem cells (iPSCs) 

• Adult stem cells (ASCs)^1,4 

When exposed to appropriate growth factors and cultured within a supportive extracellular matrix, these cells can form organoids that reproduce many structural and functional characteristics of the pancreas¹. Beyond their potential use in transplantation, organoids provide valuable platforms for biological assays, drug screening, gene profiling, gene editing, and cellular differentiation. 

Adult stem cell-derived organoids offer an additional advantage because they can generate miniature organ-like structures containing multiple pancreatic cell types rather than only β-cells. However, current canine organoids are composed predominantly of ductular cells, with relatively few glucose-responsive β-cells, highlighting an important area for further optimisation. 

From Laboratory Development to Clinical Application 

Producing functional β-like cells suitable for transplantation requires carefully controlled differentiation. Key transcription factors involved during pancreatic development—including PDX1, NKX6.1, SOX9, NGN3, MAFA, and NKX2.2- play critical roles in guiding endocrine differentiation and insulin expression. Similar developmental pathways have also been identified in dogs, where PDX1 and MAFA contribute to insulin mRNA expression^1,5. 

Additional canine approaches have included pseudoislets derived from cultured foetal pancreases and Neo-Islets composed of pancreatic islet cells combined with adipose-derived multipotent stromal cells^6,7. Following transplantation, Neo-Islets reduced blood glucose concentrations and exogenous insulin requirements in three of four dogs, although complete insulin independence was not achieved⁷. 

Practical Clinical Insights 

Cell-based therapy has the potential to transform canine T1DM management by addressing β-cell loss rather than simply replacing insulin. However, several challenges remain before these approaches can become part of everyday veterinary practice. Efficient production of mature, functional β-like cells, optimisation of differentiation protocols, development of synthetic extracellular matrices, improved biocompatible encapsulation devices, protection from immune-mediated destruction, and identification of the optimal implantation site all require further refinement [96–98]. Until these hurdles are overcome, insulin therapy remains the standard of care, but regenerative medicine continues to offer a promising direction for future canine diabetes management. 

References 

1. Oliveira FC, Voorbij AW, Pereira EC, Alves e Almeida LM, Moraes GR, De Oliveira JT, Gouw BH, Legatti SA, Kooistra HS, Spee B, Meneses AM. Treatment of Canine Type 1 Diabetes Mellitus: The Long Road from Twice Daily Insulin Injection towards Long-Lasting Cell-Based Therapy. Organoids. 2024 Apr 4;3(2):67-82. https://www.mdpi.com/2674-1172/3/2/6 

2. Paterson YZ, Kafarnik C, Guest DJ. Characterization of companion animal pluripotent stem cells. Cytometry Part A. 2018 Jan;93(1):137-48. https://onlinelibrary.wiley.com/doi/pdf/10.1002/cyto.a.23163 

3. Harrington S, Williams SJ, Otte V, Barchman S, Jones C, Ramachandran K, Stehno-Bittel L. Improved yield of canine islet isolation from deceased donors. BMC Veterinary Research. 2017 Aug 22;13(1):264. https://link.springer.com/content/pdf/10.1186/s12917-017-1177-2.pdf 

4. Clevers H. Modeling development and disease with organoids. Cell. 2016 Jun 16;165(7):1586-97. https://www.cell.com/cell/pdf/S0092-8674(16)30729-2.pdf 

5. Zhu Y, Liu Q, Zhou Z, Ikeda Y. PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration. Stem cell research & therapy. 2017 Nov 2;8(1):240. https://link.springer.com/content/pdf/10.1186/s13287-017-0694-z.pdf 

6. Czernichow P, Reynaud K, Kerr-Conte J, Furthner E, Ravassard P. Production, characterization, and function of pseudoislets from perinatal canine pancreas. Cell Transplantation. 2019 Dec;28(12):1641-51. https://journals.sagepub.com/doi/pdf/10.1177/0963689719869004 

7. Gooch A, Zhang P, Hu Z, Loy Son N, Avila N, Fischer J, Roberts G, Sellon R, Westenfelder C. Interim report on the effective intraperitoneal therapy of insulin-dependent diabetes mellitus in pet dogs using “Neo-Islets,” aggregates of adipose stem and pancreatic islet cells (INAD 012-776). PLoS One. 2019 Sep 19;14(9):e0218688. https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0218688&type=printable