Improved Cutaneous Healing in Diabetic Mice Exposed to Healthy Peripheral Circulation

Abstract

Impaired repair of skin defects is a major complication of diabetes; yet, the pathophysiology of diabetic (db) wound healing remains largely opaque. Here, we investigate the role of humoral factors in modulating db wound repair by generating chimeric animals through parabiotic joining of wild-type (wt) and diabetic (db/db) mice. This strategy allows wounds on healing-deficient db/db mice to be exposed to factors derived from the wt circulation at physiologically appropriate concentrations. When compared with db controls, chimeric db/db animals showed significantly improved healing of full-thickness, cutaneous wounds, with enhanced granulation tissue formation, angiogenesis, cell proliferation, and collagen deposition. Glycemic control was unaffected by parabiosis; however, the distribution of circulating leukocytes, altered in db controls, normalized in db-chimeras. Both wt and db cells were recruited from circulation into db wounds, but wt cells never exceeded 20% of total cells. Improved angiogenesis persisted in db-chimeras separated 24 hours after wounding, suggesting the existence of long-term normalizing factors. This study establishes a new model for studying db wound healing, and shows a key role for circulating factors in normalizing wound repair in diabetes.

Pharmacological rescue of diabetic skeletal stem cell niches

“…However, in Db mice, significantly reduced injury expansions of mSSCs and BCSPs suppressed osteogenesis and impaired healing. Several groups have reported that exposure to a young circulation rejuvenates muscle, heart, brain, and skeletal tissue (15, 25–27) and that exposure to a non-Db circulation improves Db cutaneous wound healing (16). However, we found that exposure to a non-Db circulation did not restore Db bone healing.…”

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

“…Parabiosis was performed and cross-circulation assessed in a subset of animals (n = 3 couples) from each study condition as we previously described (54). Organs were harvested 3 hours after injection from each animal for densitometric analysis to verify dye cross-circulation.…”

“…High endothelial EET levels induced a dramatic increase in number, size, and spread of distant metastases. To determine whether the systemic modulation of EET levels facilitates cancer cell dissemination at the primary tumor site (by promoting extravasation and migration) or at the metastatic site (by promoting homing, colonization, dormancy escape, and survival), we utilized a parabiosis model with a shared circulatory system (53,54), with a tumor-bearing (donor) mouse with high EET levels (Tie2-CYP2C8-Tr or sEH-null) conjoined to a non-tumor-bearing (recipient) mouse with normal or low endothelial EET levels (WT or Tie2-sEH-Tr, respectively). Other configurations served as controls.…”

Fetal microchimerism in skin wound healing

“…17 The transfer of wild type cells has been reported to improve diabetic chronic wounds in parabiotic mice. 20 It is therefore tempting to assume that normal FMCs might have beneficial effects in situations of maternal defective healing where these will display a selective advantage and possibly rescue the affected skin. 20,21 Indeed, we have previously observed the transient healing of a recalcitrant leg ulcer in a sickle cell patient during pregnancy and hypothesized that it might be due to the recruitment of healthy fetal cells from her offspring.…”

“…20 It is therefore tempting to assume that normal FMCs might have beneficial effects in situations of maternal defective healing where these will display a selective advantage and possibly rescue the affected skin. 20,21 Indeed, we have previously observed the transient healing of a recalcitrant leg ulcer in a sickle cell patient during pregnancy and hypothesized that it might be due to the recruitment of healthy fetal cells from her offspring. 22 We next hypothesized that the presence of fetal cells recruited into normal wounds during pregnancy might modify the adult maternal wound environment toward a scarless fetal-like wound healing.…”