Engineering a Humanised Niche to Support Human Haematopoiesis in Mice: Novel Opportunities in Modelling Cancer.

Alvaro Sanchez-Herrero,Maria Flandes-Iparraguirre,Jacqui A Mcgovern,Christoph A Lahr,Manuel M Mazo,Froilán Granero-Molto,Abbas Shafiee,Borja Saez,Laura J Bray,Bruno Paiva,Isabel A Calvo,Marietta Landgraf,Felipe Prosper,Elena De Juan Pardo,Andrew Nicol

doi:10.3390/cancers12082205

Abstract

Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the combination of an orthotopic humanised tissue-engineered bone construct (ohTEBC) with patient-specific bone marrow (BM) cells to create a humanised bone marrow (hBM) niche capable of supporting the engraftment of human haematopoietic cells. Results showed that this model supports the engraftment of human CD34+ cells from a healthy BM with human haematopoietic cells migrating into the mouse BM, human BM compartment, spleen and peripheral blood. We compared these results with the engraftment capacity of human CD34+ cells obtained from patients with multiple myeloma (MM). We demonstrated that CD34+ cells derived from a diseased BM had a reduced engraftment potential compared to healthy patients and that a higher cell dose is required to achieve engraftment of human haematopoietic cells in peripheral blood. Finally, we observed that hematopoietic cells obtained from the mobilised peripheral blood of patients yields a higher number of CD34+, overcoming this problem. In conclusion, this humanised mouse model has potential as a unique and patient-specific pre-clinical platform for the study of tumour–microenvironment interactions, including human bone and haematopoietic cells, and could, in the future, serve as a drug testing platform.

Highlights

Over 80% of drugs fail to obtain market approval, despite showing promising results in pre-clinical studies
For the establishment of the orthotopic humanised tissue-engineered bone construct, tubular medical-grade polycaprolactone scaffolds were printed in a custom made melt electrowritten (MEW) device, as described previously [27] (Figure 1A–C)
The culture was switched to osteogenic media to stimulate the human osteoblasts (hOBs) to secrete a mineralised extracellular matrix (ECM)

Summary

Introduction

Over 80% of drugs fail to obtain market approval, despite showing promising results in pre-clinical studies. This is mainly due to the lack of clinically predictable animal models that faithfully represent human disease [1], in the field of oncology [2]. Humanised mice emerged in an effort to overcome species differences, with animals featuring functional human cells and tissues [7]. One of the aspects that can be humanised is the haematopoietic system [8] and it has been recognised as a promising tool for unravelling the complex mechanisms that exist between the immune system and tumour cells. In the 1990s it was first reported that peripheral blood mononuclear cells (Hu-PBL-Scid) [9] and haematopoietic stem cells (HSCs) (Hu-SRC-Scid) [10]

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Conclusion