Foe turned friend: multiple functional roles attributable to hyper-activating stem cell factor receptor mutant in regeneration of the haematopoietic cell compartment

Abstract

OBJECTIVES:

Stem cell factor receptor, c-kit, is considered to be the master signalling molecule of haematopoietic stem cells. It develops the orchestral pattern of haematopoietic cell lineages, seen by its varying degree of omnipresence in progenitors, lineage committed and mature cells. We have investigated the effect of over-expressing c-kit on early recovery of the haematopoietic compartment, in irradiated hosts. MATERIALS AND METHODS:

Normal bone marrow cells (BMCs) were transfected with Kit(wt) (wild-type c-kit) or its variant Kit(mu) (asp814tyr) by electroporation. Lethally irradiated mice were transplanted with normal or transfected congeneic BMCs. The effect of ectopic expression of c-kit on haematopoietic cell recovery was determined by analysing donor-derived cells. Furthermore, effects of both types of c-kit over-expression on progenitor and lineage-committed cells were examined by flow cytometric analysis of Sca-1 and lineage-committed (Lin(+)) cells respectively. RESULTS:

Hyper-activating Kit(mu) significantly improved recovery of the haematopoietic system in irradiated hosts. In vivo results showed that the donor-derived c-kit(+) cell population was increased to more than 3-fold in the case of Kit(mu)-transfected cells compared to normal and Kit(wt) over-expressing BMCs. In general, survival of progenitor and committed cell was improved in the Kit(mu) over-expressing system compared to the other two cohorts. CONCLUSION:

These results suggest that recruitment of the hyper-activating variant of c-kit (Kit(mu)) lead to early recovery of the bone marrow of lethally irradiated mice.