Understanding Ontogeny and Optimizing Strategies to Promote Hematopoietic Engraftment Following In Utero Transplantation

Early diagnosis and in utero hematopoietic stem cell transplantation (IUHSCTx) have the potential to reduce fetal/neonatal morbidity/mortality due to hematological and immunological disorders. In some instances, IUHSCTx could also prevent disease-dependent organ damage/failure that many genetic diseases can exert during gestation. Clinical experiences show that IUHSCTx can successfully treat certain immune deficiencies. However, the relatively low levels of engraftment of hematopoietic stem cells (HSC) following IUHSCTx have precluded it from being curative for other diseases in which there is no selective advantage for the transplanted donor HSC. The goal of the projects and experiments presented in this dissertation was to build new tools and use them to develop and test novel strategies to improve IUHSCTx outcome. Here, we conducted studies to delineate the steps and key cellular elements in the emergence of the BM HSC niche, and the onset of marrow hematopoiesis during fetal life. We identified the existence of a functional human mesenchymal niche, which contributes to cartilage, bone, and vasculature, and we demonstrated that the fetal Stro-1+ cell population contains hematovascular mesoderm progenitors. Of particular note, we showed that adult Stro-1+ cells are phenotypically/functionally different from their fetal counterpart, but when placed in vivo in a fetal environment, they reprogram to a more primitive phenotype, and generate HSCs capable of robust, serial, multilineage hematopoietic reconstitution. By studying the HSC niche during ontogeny, we also identified a highly potent hematopoietic stem/progenitor cell (HSPC) subpopulation (CD166+CD34+), which we then found are also present within the adult-BM. We demonstrated that fetal CD166+CD34+ cells from different organs are functionally different, and also found that adult BM CD166+CD34+ cells are exclusively hematopoietic, and, surprisingly, possess higher clonogenic potential compared with their fetal counterparts. Finally, using the ovine model of in utero transplantation, we demonstrated that manipulation/priming of the fetal HSC niches, by transplanting adult stromal/ endothelial cells prior to IUHSCTx, improves the outcome of IUHSCTx significantly. Taken together, studying fetal HSCs niches during development and adult life, we identified a primitive HSC population with high clonogenic potential, which could be used as a source of highly enriched HSCs to treat/cure a broad variety of blood disease, and also discovered a unique non-hematopoietic, epigenetically primed, adult somatic cell that is able to generate functional HSC in vivo. We also showed that creating adult-BM-derived HSC niches in the fetal microenvironment significantly improves IUHSCTx outcome, increasing donor hematopoietic engraftment to levels that would likely be therapeutic in many of the major genetic diseases.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2015

Author dc:creator

• Mokhtari, Saloomeh

• in utero transplantation

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/57253

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/57253