Article

An in vivo model to study and manipulate the hematopoietic stem cell niche

Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Blood (Impact Factor: 10.45). 04/2010; 115(13):2592-600. DOI: 10.1182/blood-2009-01-200071
Source: PubMed

ABSTRACT

Because the microenvironment that supports hematopoietic stem cell (HSC) proliferation and differentiation is not fully understood, we adapted a heterotopic bone formation model as a new approach for studying the HSC microenvironment in vivo. Endogenous HSCs homed to tissue-engineered ossicles and individually sorted HSCs from ossicles were able to reconstitute lethally irradiated mice. To further explore this model as a system to study the stem cell niche, ossicles were established with or without anabolic parathyroid hormone (PTH) treatment during the 4-week course of bone development. Histology and micro-computed tomography showed higher bone area-to-total area ratios, thicker cortical bone and trabecular bone, significantly higher bone mineral density and bone volume fraction in PTH-treated groups than in controls. By an in vivo competitive long-term reconstitution assay, HSC frequency in the ossicle marrow was 3 times greater in PTH groups than in controls. When whole bone marrow cells were directly injected into the ossicles after lethal irradiation, the PTH-treated groups showed an enhanced reconstitution rate compared with controls. These findings suggest the residence of HSCs in heterotopic bone marrow and support the future use of this ossicle model in elucidating the composition and regulation of the HSC niche.

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    • "Moreover, some of these studies show none or only small amounts of mineralized tissue formation e not a fully regenerated organ bone e and often the newly formed bone and marrow compartment is interspersed with large volumes of scaffold material, which interferes with the development of a coherent physiological tissue network [18] [19]. Importantly, most current models investigating hematopoietic niche physiology fail to recapitulate the processes seen in humans as they analyse the behaviour and function of murine e and not human e HSCs within their niches [16] [17] [20]. "
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    • "With a better understanding of biomaterials and stem cells, a number of new ectopic transplant models have been proposed recently as useful tools to examine roles of microenvironment in stem cell biology. One study performed subcutaneous transplantation of mouse marrow stromal cells (MSCs) encapsulated in gelatin sponges to form an ossicle, but microvessel density, lineage number, and HSC/P number in the ossicle proves to be far lower than in the femur (Song et al., 2010 ). Interestingly, adipocyte number is 30- fold higher in the ossicle than the femur, consistent with a previous observation that marrow adipocytes negatively regulate HSC number and engraftment (Naveiras et al., 2009). "
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