Xenotransplantation of neonatal porcine bone marrow‐derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis

Abstract

Background The clinical utility of stem cell therapy for peripheral artery disease has not been fully discussed, and one obstacle is limited donor supplies. In this study, we attempted to rescue mouse ischemic hind limb by xenotransplantation of neonatal porcine bone marrow‐derived mesenchymal stem cells (npBM‐MSCs). Methods Neonatal porcine bone marrow‐derived mesenchymal stem cells were transplanted to ischemic hind limbs of male C57BL/6J mice (npBM‐MSCs group). Mice with syngeneic transplantation of mouse BM‐MSCs (mBM‐MSCs group) were also prepared for comparison. The angiogenic effects were evaluated by recovery of blood flow on laser Doppler imaging, histologic findings, and genetic and protein levels of angiogenic factors. Results Regarding laser Doppler assessments, blood flow in the hind limb was rapidly recovered in the npBM‐MSCs group, compared with that in the mBM‐MSCs group (P = .016). Compared with the mBM‐MSCs group, the npBM‐MSCs group had early and prominent lymphangiogenesis [P < .05 on both post‐operative days (PODs) 3 and 7] but had similar angiogenesis. Regarding genomic assessments, xenotransplantation of npBM‐MSCs enhanced the expressions of both porcine and murine Vegfc in the hind limbs by POD 3. Interestingly, the level of murine Vegfc expression was significantly higher in the npBM‐MSCs group than in the mBM‐MSCs group on PODs 3 and 7 (P < .001 for both). Furthermore, the secreted VEGFC protein level was higher from npBM‐MSCs than from mBM‐MSCs (P < .001). Conclusion Xenotransplantation of npBM‐MSCs contributed to the improvement of hind limb ischemia by both angiogenesis and lymphangiogenesis, especially promotion of the latter. npBM‐MSCs may provide an alternative to autologous and allogeneic MSCs for stem cell therapy of critical limb ischemia.

Xenotransplantation of neonatal porcine bone marrow–derived mesenchymal stem cells improves diabetic wound healing by promoting angiogenesis and lymphangiogenesis

“…We previously clarified that npBM-MSCs were characterized by super-rapid growth, a small size, and a robust proliferation profile 36 and elucidated that xenotransplantation of npBM-MSCs improved murine hind limb ischemia through angiogenesis and lymphangiogenesis. 22 Therefore, the promotion of neonatal porcine granulation. 37 TGF-β expression was decreased in a diabetic ulcer animal model, 38 and inhibition of this cytokine activates inflammatory cells, delaying the proliferation phase of the wound healing process.…”

“…Therefore, we promote the assessments of neonatal pig as a suitable donor for clinical usage. We previously clarified that npBM‐MSCs were characterized by super‐rapid growth, a small size, and a robust proliferation profile 36 and elucidated that xenotransplantation of npBM‐MSCs improved murine hind limb ischemia through angiogenesis and lymphangiogenesis 22 . Therefore, the promotion of neonatal porcine MSCs is considered as an excellent strategy for future xenotransplantation in clinical settings.…”

Development and characterization of Gal KO porcine bone marrow‐derived mesenchymal stem cells

“…3 Recently, we demonstrated that the porcine-derived MSCs improved critical ischemic limb disease in rat model more efficiently compared with human MSCs. 4 On the other hand, since porcine MSC is xenogeneic against human, the implanted MSCs could be eliminated by the xenogeneic rejection. antigens as efficiently as human MSCs do.…”

“…3 Recently, we demonstrated that the porcine bone marrowderived MSC could more effectively improve critical ischemic limb disease in rat model compared with human MSCs. 4 Even porcine bone marrow-derived MSC improved the ischemic limb disease in rat model, porcine cells present alpha-Gal which could cause xenogeneic rejection. Elimination of alpha-Gal might improve the efficacy of porcine bone marrow-derived MSC by mitigating xenogeneic rejection of implanted MSCs.…”

The Impact of Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease

“…Herein, people turn to utilize the xenograft of porcine MSCs. Yamada et al [ 79 ] proposed that xenotransplantation of porcine bone marrow MSCs contributed to the improvement of mouse hind limb ischemia through both angiogenesis and especially lymphangiogenesis, showing the potential of being an alternative source for stem cell therapy ( Table 1 ). Nevertheless, a lack of direct evidence that confirmed the incorporation of MSCs into lymphangiogenesis is flawed, which means we cannot rule out the disturbance of the paracrine effect.…”