Nov/CCN3 Enhances Cord Blood Engraftment by Rapidly Recruiting Latent Human Stem Cell Activity

Umbilical cord blood (UCB) has had considerable impact in pediatric stem cell transplantation, but its wider use is limited in part by unit size. Long-term ex vivo culture offers one approach to increase engraftment capacity by seeking to expand stem and progenitor cells. Here, we show brief incubation (8 h) of UCB CD34+ cells with the matricellular regulator Nov (CCN3) increases the frequency of serially transplantable hematopoietic stem cells (HSCs) 6-fold. This rapid response suggests recruitment rather than expansion of stem cells; accordingly, in single-cell assays, Nov increases the clonogenicity of phenotypic HSCs without increasing their number through cell division. Recruitment is associated with both metabolic and transcriptional changes, and tracing of cell divisions demonstrates that the increased clonogenic activity resides within the undivided fraction of cells. Harnessing latent stem cell potential through recruitment-based approaches will inform understanding of stem cell state transitions with implications for translation to the clinic.