The microglial challenge to encapsulated cell mediated drug delivery in brain tissue

Abstract Background Dementia disorders affect millions of people worldwide, among which Alzheimer’s disease (AD) accounts for 60% cases. Treatment of these disorders are constrained due to inefficient brain availability of peripherally administered drugs. Conversely, direct intracerebroventricular injections are counterintuitive due to unspecific side‐effects. Recently, Aducanumab has shown potential to clear amyloid plaques from AD brain, but its efficacy to revive clinical symptoms are under debate. In this regard, direct delivery of regenerative biological drugs utilizing encapsulated cell biodelivery (ECB) has gained much attention. Conversely, how the pathological microenvironment of the AD brain affects these encapsulated drug‐delivering cells are scarcely understood. The ECB approach nullifies immune reaction from host tissue by protecting drug‐delivering cells from direct physical contact with the host tissue. Thus, in this study we probe the effect of factors released from activated human microglial cells (HMC3 cell line) on ECB devices harboring nerve growth factor (NGF) releasing cells (NGC0211; modified human ARPE‐19 cells). Method ECB devices harboring NGC0211 cells were manufactured and maintained in DMEM/F12 culture medium containing 10% serum until used. HMC3 cells were activated using AD related molecules including 1µM amyloid beta (Aβ 40 and Aβ 42 ) peptides and 10ng/mL inflammatory cytokines (interferon‐γ, IFN‐γ; interleukin‐1β, IL‐1β; or both) for 24hrs, and a cell free microglia conditioned medium (MCM) was obtained. ECB devices were then exposed to various MCMs, and NGF release was followed for several weeks assessed by ELISA (DY256, R&D systems). Similarly, non‐encapsulated NGC0211 cells grown in multi‐well slides were exposed to MCMs and cellular proliferation (Ki67 expression) along with senescence parameters (SA‐β‐galactosidase) were evaluated. Result We found that factors released from activated microglia hampered NGF release from ECB devices. Simultaneously, MCMs reduced Ki67 expression and elevated SA‐β‐galactosidase activity in NGC0211 cells. Conclusion Activated microglia, a common feature of all neurodegenerative conditions, impair NGF release, cellular proliferation and induce senescence in NGC0211 cells. Similar impact of microglia on other types of drug‐delivering cells (stem cells or genetically modified) needs to be studied. Our study highlights one of the probable underlying causes for impaired long‐term cell mediated drug delivery in neurodegenerative diseases and helps guide improvements in the technologies.