Pharmacological Mobilization of Endogenous Stem Cells Significantly Promotes Skin Regeneration after Full-Thickness Excision: The Synergistic Activity of AMD3100 and Tacrolimus

Abstract

Stem cell therapy has shown promise in treating a variety of pathologies including skin wounds, but practical applications remain elusive. Here we demonstrate that endogenous stem cell mobilization produced by AMD3100 and low-dose Tacrolimus is able to reduce by 25% the time of complete healing of full-thickness wounds created by surgical excision. Equally important, healing was accompanied by reduced scar and regeneration of hair follicles. Searching for mechanisms, we found that AMD3100 combined with low-dose Tacrolimus mobilized increased number of lineage-negative c-Kit+, CD34+ and CD133+ stem cells. Low-dose Tacrolimus also increased the number of SDF-1 bearing macrophages in the wounds sites amplifying the “pull” of mobilized stem cells into the wound. Lineage tracing demonstrated the critical role of CD133 stem cells in enhanced capillary and hair follicle neogenesis contributing to more rapid and perfect healing. Our findings offer a significant therapeutic approach to wound healing and tissue regeneration.

Chimeric Allografts Induced by Short‐Term Treatment With Stem Cell Mobilizing Agents Result in Long‐Term Kidney Transplant Survival Without Immunosuppression: II, Study in Miniature Swine

“…Mobilization of endogenous stem cells with AMD3100 and low-dose FK506 results in immunosuppressive-free long-term survival in maximally immunologically mismatched swine Similar to our reports in rodents (27,28), subcutaneous injection of AMD3100 (1 mg/kg) plus low-dose FK506 (0.03 mg/kg) in swine significantly increased CD34 + stem cells in peripheral blood. CD34 + stem cells reached peak levels in peripheral blood at 3 h and remained at higher levels up to 48 h after the dual-drug injection ( Figure 1A).…”

“…In a rat kidney transplant model (29), we have shown that FK506 alone increased SDF-1 presence in the transplant. We have reported that cells with macrophage phenotypes are liberated from the bone marrow by FK506 and recruited to the injured sites (27,28 It has been reported that rejection of donor skin grafts occurred in 9-11 days in long-term specific tolerance to one haplotype class I plus minor antigen disparate renal allografts in miniature swine (33). Coincident with skin rejection, most animals developed a transient rise in creatinine to 4.9 AE 1.2 mg/dL (n = 10), with normal levels returning in all animals within 2 weeks.…”

“…Our researchers made the generation of donor organ chimerism and immunomodulation more efficient after the discovery that low-dose FK506 and the chemokine (C-X-C motif) receptor (CXCR)4 inhibitor AMD3100 have synergistic actions in the mobilization of bone marrow-derived stem cells (27,28). Further, reducing exogenous immunosuppression to subtherapeutic levels allowed rejection to occur in our model at rates adequate to facilitate stem cell help/replacement and to preserve graft function.…”

The Role of Chemokines in Mesenchymal Stem Cell Homing to Wounds

“…This antagonist is already being used in the clinic to stimulate mobilization of hematopoietic stem cells from the bone marrow into the blood in cancer patients. 48 A recent study demonstrates that local injection of AMD3100 at the site of injury increases recruitment of endothelial progenitor cells to wounds in rodent models. 48 An important advantage of administering either SDF-1 or AMD3100 to the wound is that it directly targets endogenous stem cells and circumvents the challenges with isolating, expanding, and then delivering stem cells to the wound.…”

“…48 A recent study demonstrates that local injection of AMD3100 at the site of injury increases recruitment of endothelial progenitor cells to wounds in rodent models. 48 An important advantage of administering either SDF-1 or AMD3100 to the wound is that it directly targets endogenous stem cells and circumvents the challenges with isolating, expanding, and then delivering stem cells to the wound. However, if the goal is to also recruit exogenous MSC then recognized challenges associated with MSC delivery to the wound need to be overcome.…”