| First Author | Campbell CJ | Year | 2010 |
| Journal | Blood | Volume | 116 |
| Issue | 9 | Pages | 1433-42 |
| PubMed ID | 20525924 | Mgi Jnum | J:164522 |
| Mgi Id | MGI:4834084 | Doi | 10.1182/blood-2009-12-258095 |
| Citation | Campbell CJ, et al. (2010) The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for self-renewal capacity. Blood 116(9):1433-42 |
| abstractText | The molecular basis for the unique proliferative and self-renewal properties that hierarchically distinguish human stem cells from progenitors and terminally differentiated cells remains largely unknown. We report a role for the Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) as an indispensable regulator of self-renewal in human stem cells and show that a functional dependence on Mcl-1 defines the human stem cell hierarchy. In vivo pharmacologic targeting of the Bcl-2 family members in human hematopoietic stem cells (HSCs) and human leukemic stem cells reduced stem cell regenerative and self-renewal function. Subsequent protein expression studies showed that, among the Bcl-2 family members, only Mcl-1 was up-regulated exclusively in the human HSC fraction on in vivo regeneration of hematopoiesis. Short hairpin RNA-knockdown of Mcl-1 in human cord blood cells did not affect survival in the HSC or hematopoietic progenitor cell fractions in vitro but specifically reduced the in vivo self-renewal function of human HSCs. Moreover, knockdown of Mcl-1 in ontogenetically primitive human pluripotent stem cells resulted in almost complete ablation of stem cell self-renewal function. Our findings show that Mcl-1 is an essential regulator of stem cell self-renewal in humans and therefore represents an axis for therapeutic interventions. |
