Implantable microenvironments to attract hematopoietic stem/cancer cells

Abstract

The environments that harbor hematopoietic stem and progenitor cells are critical to explore for a better understanding of hematopoiesis during health and disease. These compartments often are inaccessible for controlled and rapid experimentation, thus limiting studies to the evaluation of conventional cell culture and transgenic animal models. Here we describe the manufacture and image-guided monitoring of an engineered microenvironment with user-defined properties that recruits hematopoietic progenitors into the implant. Using intravital imaging and fluorescence molecular tomography, we show in real time that the cell homing and retention process is efficient and durable for short-and longterm engraftment studies. Our results indicate that bone marrow stromal cells, precoated on the implant, accelerate the formation of new sinusoidal blood vessels with vascular integrity at the microcapillary level that enhances the recruitment hematopoietic progenitor cells to the site. This implantable construct can serve as a tool enabling the study of hematopoiesis.

Engineering of a functional bone organ through endochondral ossification

“…Furthermore, on the basis of the concept of mutual influences between the BM microenvironment and leukemia cells (27,28), the possibility of establishing a human origin BM microenvironment in humanized hematopoietic murine models (29)(30)(31) has a large relevance to investigate the development and progression of blood cell malignancies. Last but not least, the generation of an extramedullary bone organ, accessible to advanced imaging techniques (e.g., intravital confocal microscopy) (14), opens the perspective to investigate and exploit processes underlying the efficient expansion of HSCs for therapeutic purposes (13).…”

“…Interestingly, using mouse embryonic limb-derived MSCs it was reported that the endochondral ossification process is required for the formation of an adult HSC niche (12), consistent with the onset of hematopoiesis at the sites of hypertrophic cartilage remodeling in long bones during skeletal growth (2). To the best of our knowledge, despite phenotypical evidence of the presence of putative HSCs within reconstituted ossicles (12)(13)(14), engineering of a human cell-induced bone organ hosting fully functional hematopoiesis has not yet been achieved.…”

Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro

“…Therefore, studies on hematopoiesis commonly rely on animal models to ensure the presence of an intact bone marrow microenvironment that enables normal physiologic marrow responses [12][13][14][15] . Furthermore, although it has been reported that bone marrow can be engineered in vivo [16][17][18][19] , no method exists to culture engineered bone marrow in vitro. To bridge the functional gap between in vivo and in vitro systems, we developed a method to produce a "bone marrow-on-a-chip" culture system that contains artificial bone and a living marrow, which is first generated in mice, and then explanted whole and maintained in vitro within a microfluidic device.…”

Human Bone Xenografts: from Preclinical Testing for Regenerative Medicine to Modeling of Diseases

“…For example, novel and powerful imaging modalities have been developed to observe vascular development, in order to shed light on angiogenic process following implantation of engineered bone tissues [2,3]. Advances in multimodal imaging have also made it possible to concurrently monitor such responses in parallel [4] and/or multiple cell types homing and migrating to the implanted constructs [5].…”