*Purpose: AIPCs (Activated Islet Proliferating Cells) are a recently developed cell population generated from isolated islets of mice and humans. AIPCs are over 65% CD133-, Ki67- and insulin-triple-positive, and are over 70% double-positive for both insulin and glucagon. They secrete both hormones in response to secretagogues and can be expanded in vitro for long periods of time (over 200 days). AIPCs engraft, survive and secrete insulin when implanted into a kidney capsule, and are non-oncogenic. It has been previously shown that expression of the stem cell marker CD133 correlates with the capacity of cells to engraft long-term, and these cells have the innate capability to migrate and home to injury sites. We, therefore, hypothesized that AIPCs can migrate into the pancreas and normalize hyperglycemia when injected into a STZ-diabetic mouse intravenously (IV).

*Methods: To test this, six STZ-treated mice were injected IV with 4 million AIPCs isolated from tomato-Red mice (Jax, trAIPCs). On days 28 and 42 post-injection, two animals per time point were sacrificed and their tissue analyzed for cellular engraftment.

*Results: On day 28, all mice were still hyperglycemic (average FBG 396mg/dl); by day 42, FBG levels had decreased in all injected animals (average FBG 320 mg/dl), with one of the four followed-up animals with FBG as low as 224mg/dl. On day 46, the remaining two animals received an additional IV injection of 10 million cells. Following the second injection, both animals achieved FBG levels < 200mg/dl (average 188mg/dl, day 56) and remained in this range until day 70 when sacrificed. Tissue analysis showed that AIPCs had homed and engrafted into the pancreas of treated animals and displayed no signs of oncogenesis. In a subsequent experiment, eight STZ-diabetic mice were injected IV with 10 million trAIPCs. Within 32 days post-injection, all treated animals showed lower FBG levels, while control animals maintained FBG over 400mg/dl. Throughout the 100-day study, FBG levels of treated animals steadily decreased to an average of 286mg/dl. In a third experiment, 20 million trAIPCs were injected IV into STZ diabetic mice (n=4). By day 16, all mice had lower FBG levels, with two of the animals at 199 and 244mg/dl, which further decreased to 168 and 209mg/dl by day 50.

*Conclusions: Though preliminary and ongoing, these studies demonstrate several key findings: AIPC injection is safe and can be administered repeatedly with no deleterious effects; a critical mass of cells must be reached to efficiently normalize glucose levels; AIPCs home and engraft to the pancreas when injected IV and can effectively treat hyperglycemia.

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