Establishing human leukemia xenograft mouse models by implanting human bone marrow–like scaffold-based niches

Abstract

To begin to understand the mechanisms that regulate self-renewal, differentiation, and transformation of human hematopoietic stem cells or to evaluate the efficacy of novel treatment modalities, stem cells need to be studied in their own species-specific microenvironment. By implanting ceramic scaffolds coated with human mesenchymal stromal cells into immune-deficient mice, we were able to mimic the human bone marrow niche. Thus, we have established a human leukemia xenograft mouse model in which a large cohort of patient samples successfully engrafted, which covered all of the important genetic and risk subgroups. We found that by providing a humanized environment, stem cell self-renewal properties were better maintained as determined by serial transplantation assays and genome-wide transcriptome studies, and less clonal drift was observed as determined by exome sequencing. The human leukemia xenograft mouse models that we have established here will serve as an excellent resource for future studies aimed at exploring novel therapeutic approaches.

Versatile humanized niche model enables study of normal and malignant human hematopoiesis

“…Overall, our work describes a versatile humanized niche model for studying both normal and leukemic human hematopoietic cell biology, particularly for the less aggressive subtypes that fail to engraft in NSG mice. Recent reports demonstrate the use of humanized bone ossicles for the study of malignant hematopoiesis (11)(12)(13)(14)(15)(16). Nevertheless, in all of these models, hMSCs were first induced to form bone ossicles before malignant hematopoietic cells were injected intrascaffold, making the duration of the whole experiment between 20 and 34 weeks compared with only 10 to 12 weeks in our study.…”

“…By merging knowledge from biomaterials, tissue engineering, and cell-implantation fields, investigators have generated new models to mimic the native human hematopoietic microenvironment within s.c. 3D structures (4)(5). Using human mesenchymal stromal cells (hMSCs) as stromal cell support within bone-forming implants, researchers have studied normal (6)(7)(8)(9)(10) and malignant (11)(12)(13)(14)(15)(16) hematopoiesis.…”

Acute myeloid leukemia including favorable-risk group samples engraft in NSG mice: just be patient

“…Supporting the notion that engraftment could be impaired by cross-species differences, Majeti's group, JJ Schuringa's group and Bonnet's group reported in parallel the feasibility of engrafting previously "non-engrafter" AML samples by implanting a three-dimensional humanized bone marrow stroma scaffold/ossicles. [11][12][13] In this humanized microenvironment, non-engrafter samples were able to engraft with a shorter latency than that reported by Paczulla et al, further suggesting that long-latency engrafters might be more sensitive to microenvironmental signals than "engrafters".…”

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

“…153 Likewise, several laboratories are developing 3-dimensional (3D) niche models that mimic human bone structure and composition to propagate primary specimens both in vitro and in vivo upon implantation to mice. Such models were successfully used to engraft AMLs, blast crisis CML, [154][155][156] and a limited number of MPNs (myelofibrosis). 157 These emerging models represent invaluable and cost-effective platforms for preclinical studies.…”