The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1.

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Summary Introduction Post-mastectomy breast reconstruction has become an increasingly important component of breast cancer treatment. Unfortunately, some patients experience severe postoperative pain, placing them at risk for increased clinical morbidity and the development of disabling chronic pain. In an attempt to identify at-risk patients, we prospectively evaluated patient characteristics and medical/surgical variables associated with more severe acute post-reconstruction pain. Methods Women (N = 2207; one-week 82.8% response rate) undergoing breast reconstruction were assessed for pain experience, anxiety, depression, and sociodemographic characteristics prior to surgery. Pain assessments were made preoperatively and postoperative at 1-week using validated survey instruments including the McGill Pain Questionnaire-Short Form (MPQ-SF), Numerical Pain Rating Scale (NPRS), and BREAST-Q Chest and Upper Body scale. Depressive symptoms and anxiety severity were assessed by the Patient Health Questionnaire and Generalized Anxiety Disorders Scale, respectively. Mixed-effects regression modeling was used to examine the relationships between patient characteristics and medical/surgical factors and 1-week postoperative pain. Results Younger age, bilateral reconstruction, and severity of preoperative pain, anxiety and depression were all associated with more severe acute postoperative pain on all the pain measures and BREAST-Q. Comparison of surgical procedure type indicated less severe postoperative pain for PTRAM, DIEP and SIEA reconstructive surgery compared to tissue expander/implant reconstruction. Conclusions This study identified patients at risk for greater acute postoperative pain following breast reconstruction. These findings will allow plastic surgeons to better tailor postoperative care to improve patient comfort, reduce clinical morbidity, and further enhance patient satisfaction with their surgical outcome.

The proportion of U.S. plastic surgeons with a high-volume autologous or microsurgical breast reconstruction practice is low. Involvement with resident education appears to facilitate both, whereas time constraints and reimbursement are primary deterrents. Future efforts should focus on improving the feasibility and accessibility of all types of breast reconstruction.