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Trafficking of Grafted Pancreatic Islets Into the Brain Lateral Ventricles

Implications for Cognition

Bloch, Konstantin, PhD1; Dar, Shira2; Vanichkin, Alexey3; Gil-Ad, Irit2; Vardi, Pnina1; Weizman, Abraham, MD2,4

doi: 10.1097/TP.0000000000002671
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1 Laboratory of Diabetes and Obesity Research, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel.

2 Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel.

3 Laboratory of Transplantation, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel.

4 Research Unit, Geha Mental Health Center, Petah Tikva, Israel.

Received 17 January 2019. Revision received 29 January 2019.

Accepted 1 February 2019.

The authors declare no funding or conflicts of interest.

All participated in research design. K.B. and S.D. participated in performing histology studies. A.V. participated in performing surgery. K.B., I.G.-A., P.V., and A.W. participated in the writing of the paper.

Correspondence: Konstantin Bloch, PhD, Laboratory of Diabetes and Obesity Research, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Beilinson Campus, Petah Tikva 49100, Israel. (kbloch@clalit.org.il).

There is a tremendous interest in insulin delivery to the brain for the treatment of Alzheimer’s disease (AD). Recently, we showed increased insulin content in the brain and improved cognitive functions in a rat model of sporadic AD following transplantation of pancreatic islets in the cranial subarachnoid space (cSAS).1 However, it remains unclear whether the islets grafted in the cSAS can migrate to other brain regions. Here, we report islet trafficking from cSAS to the brain ventricular system in a rat AD-like model induced by injection of streptozotocin into lateral ventricles (LVs), followed by islet transplantation in cSAS, as described previously.1 The cognitive improvement of the AD-like rats persisted for 6 months after transplantation (unpublished data), and viable syngeneic islets were identified in the cortex, olfactory bulb, and in the LVs (Figure 1A–C). The islets detected in the LVs expressed insulin, glucagon, proinsulin, and glucose transporter 2 (Figure 1D–F). It is likely that the grafted islets migrated across the cSAS from the transplantation site to the LVs. The islet migration could be triggered by cerebrospinal fluid flow and facilitated by expansion of brain ventricles after intraventricular administration of streptozotocin.2 Another possibility is a targeted migration of grafted islets toward the streptozotocin-induced injury to the LVs endothelial lining, where they secreted insulin and other reparative factors. Such tropism toward remote injured tissue is typical for neural stem cells.3 Our results provide new insights and strategies for cell delivery to the brain for therapy of neurodegenerative cognitive dysfunctions.

FIGURE 1

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REFERENCES

1. Bloch K, Gil-Ad I, Vanichkin A, et al. Intracranial transplantation of pancreatic islets attenuates cognitive and peripheral metabolic dysfunctions in a rat model of sporadic Alzheimer’s disease. J Alzheimers Dis. 2018;65(4):1445–1458.
2. Kraska A, Santin MD, Dorieux O, et al. In vivo cross-sectional characterization of cerebral alterations induced by intracerebroventricular administration of streptozotocin. PLoS One. 2012;7(9):e46196.
3. Aboody KS, Brown A, Rainov NG, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A. 2000;97(23):12846–12851.
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