An immune cell spray (ICS) formulation allows for the delivery of functional monocyte/macrophages

Valerie Beneke,Juliane Wilhelmine Schott,Fennja Küster,Anna-Lena Neehus,Mania Ackermann,Dorothee Walter,Armin Braun,Christina Hesse,Anna Rafiei Hashtchin,Kathrin Haake,Elena Lopez-Rodriguez,Nico Lachmann,Willem F Wolkers

doi:10.1038/s41598-018-34524-2

Abstract

Macrophages are key cells of the innate immune system and act as tissue resident macrophages (TRMs) in the homeostasis of various tissues. Given their unique functions and therapeutic use as well as the feasibility to derive macrophages in vitro from hematopoietic stem cell (HSC) sources, we propose an “easy-to-use” immune cell spray (ICS) formulation to effectively deliver HSC-derived macrophages. To achieve this aim, we used classical pump spray devices to spray either the human myeloid cell line U937 or primary murine HSC-derived macrophages. For both cell types used, one puff could deliver cells with maintained morphology and functionality. Of note, cells tolerated the spraying process very well with a recovery of more than 90%. In addition, we used osmotic preconditioning to reduce the overall cell size of macrophages. While a 800 mosm hyperosmolar sucrose solution was able to reduce the cell size by 27%, we identified 600 mosm to be effective to reduce the cell size by 15% while maintaining macrophage morphology and functionality. Using an isolated perfused rat lung preparation, the combinatorial use of the ICS with preconditioned and genetically labeled U937 cells allowed the intra-pulmonary delivery of cells, thus paving the way for a new cell delivery platform.

Highlights

Macrophages are hematopoietic cells of the myeloid lineage and represent important regulators of the innate immune system as well as key players in tissue homeostasis
With the objective to develop an immune cell spray (ICS) for the local administration of macrophages either onto the skin or directly into the lung environment, we demonstrate the efficient use of a classical pump spray device to spray myeloid cell lines as well as primary murine bone marrow-derived monocytes (BMDMs)
We introduce an immune cell spray (ICS) formulation which would allow for the local delivery of macrophages to skin or lung respectively

Summary

Introduction

Macrophages are hematopoietic cells of the myeloid lineage and represent important regulators of the innate immune system as well as key players in tissue homeostasis. Macrophages can be found in a multitude of organs (referred to as tissue resident macrophages; TRMs), for example as microglia in the brain, Langerhans cells in the skin, Kupffer cells in the liver, or as alveolar macrophages (AMs) in the lungs The latter are of great therapeutic interest, as AMs play an important role in lung tissue integrity by sensing pathogens, regulating immune responses and thereby contributing to tissue homeostasis, protection and repair[1]. After infiltration of the respective organ, BMDMs are able to adapt to the instructive tissue environment and gain the functional and transcriptional fingerprint of the resident macrophage population[5,6] This exceptional, stem cell-like plasticity renders bone marrow-derived monocytes/macrophages an attractive target population for cell therapeutic approaches. We demonstrate the efficient local administration of shrunken cells into a perfused rat lung via a micro sprayer device, paving the way for macrophage cell spray formulations

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