Impact of enhanced mobilization of bone marrow derived cells to site of injury

Abstract

Background: Bone marrow derived cells (BMDC) and mesenchymal stem cells (MSC) are necessary for healing of injured tissues. Intravenous granulocyte-colony stimulating factor (G-CSF) is known to induce mobilization of BMDC to peripheral blood and the tissue levels of the stromal cell derived factor-1 (SDF-1) to be key in their homing to sites of injury. We hypothesized that injection of SDF-1 to the site of injury and/or systemic administration of G-CSF increases homing of BMDC and improves healing of traumatic injury. We also postulated that increased homing of MSC alone to sites of injury would also improve tissue healing.

Methods: Male Sprague-Dawley rats were subjected to unilateral lung contusion (LC) and assigned to the following groups: LC + injection of SDF-1 (LC + SDF-1) in the contused lung, pretreatment with systemic G-CSF for 5 days followed by either LC alone (LC + G-CSF) or by LC + injection of SDF-1 (LC + SDF-1/G-CSF). Rats in the MSC group were subjected to LC followed by systemic injection of MSC (LC + MSC). Unmanipulated controls and LC + local injection of saline (LC + saline) served as controls. Lung injury was assessed on days 1 and 5 postinjury using a histologic Lung Injury Score. BMDC and MSC homing were assessed on day 1 by hematopoietic progenitor cell (CFU-GEMM, BFU-E, and CFU-E) colony growth and immunofluorescence tracking of tagged MSC in the injured lung, respectively.

Results: Both LC + SDF-1 and LC + G-CSF had increased hematopoietic progenitor cell colony growth in the injured lung, and their combination (LC + SDF-1/G-CSF) was additive when compared with LC + saline (18 ± 3, 24 ± 3, 32 ± 3; 21 ± 3, 36 ± 10, 36 ± 3; 31 ± 4, 44 ± 10, 53 ± 5 vs. 6 ± 2, 11 ± 3, 17 ± 4; *p < 0.05). Tagged MSC were tracked predominantly in the contused lung versus the non-contused lung (7 ± 3 vs. 3 ± 2, N° MSC/HPF; *p < 0.05). Lung Injury Score on day 5 after injury was significantly lower in the LC + SDF-1, LC + G-CSF, LC + SDF-1/G-CSF and LC + MSC groups versus LC + saline (1 ± 0.6, 0.7 ± 0.5, 1 ± 0.9, 1.1 ± 0.9 vs. 3.1 ± 0.8; *p < 0.05).

Conclusion: Local SDF-1 and/or systemic G-CSF can effectively increase BMDC homing to sites of traumatic injury in an additive way and improve wound healing. This process appears to be mediated predominantly through MSC. Additional investigations are needed to identify the optimal adjuncts to improve wound healing following severe traumatic injury.