The perlecan fragment LG3 regulates homing of mesenchymal stem cells and neointima formation during vascular rejection.

Transplant vasculopathy is associated with neointimal accumulation of recipient-derived mesenchymal stem cells. Increased circulating levels of LG3, a C-terminal fragment of perlecan, were found in renal transplant patients with vascular rejection. Here, we evaluated whether LG3 regulates the migration and homing of mesenchymal stem cells and the accumulation of recipient-derived neointimal cells. Mice were transplanted with a fully-MHC mismatched aortic graft followed by intravenous injection of recombinant LG3. LG3 injections increased neointimal accumulation of α-smooth muscle actin positive cells. When green fluorescent protein (GFP)-transgenic mice were used as recipients, LG3 injection favored accumulation of GFP+ cells to sites of neointima formation. LG3 increased horizontal migration and transmigration of mouse and human MSC in vitro and led to increased ERK1/2 phosphorylation. Neutralizing ß1 integrin antibodies or use of mesenchymal stem cells from α2 integrin-/- mice decreased migration in response to recombinant LG3. Reduced intima-media ratios and decreased numbers of neointimal cells showing ERK1/2 phosphorylation were found in α2-/- recipients injected with recombinant LG3. Collectively, our results suggest that LG3, through interactions with α2ß1 integrins on recipient-derived cells leading to activation of ERK1/2 and increased migration, favors myointimal thickening.

Too old to learn?

C.J. Albert, the head of family-owned Armor Coat Insurance, is just settling in on a Sunday evening when the receives an unsettling phone call from his star salesman. Fifty-two-year-old Ed McGlynn has just returned from a business dinner with his younger technology mentor, and he's none too happy with the way he's being treated. If C.J. doesn't take this attack dog off him, Ed warns, he's gone. C.J. had indeed assigned 28-year-old Roger Sterling--the company's monomaniacal, slightly antisocial director of e-commerce--to teach Ed about digital strategy and the Web. Reverse mentoring seemed like a good way to create synergy between the sales and technology groups. The goal was to create a digital insurance product that would allow Armor Coat to keep up with its competitors. But there'd been tension between Ed and Roger right from the start--stemming from their personalities and their two departments. So when the two reluctantly agreed to meet for dinner to talk, the conversation didn't go well. Ed insisted that great sales reps, not the Internet, are crucial to selling insurance. Roger insisted that the Web will revolutionize the way insurance is sold and distributed--that Ed either give in or move on. Ed took off in a huff and subsequently phoned C.J. Roger followed Ed's irate call with his own weary ultimatum: "Either Ed goes or I go." C.J. faces some difficult Monday-morning discussions with both disgruntled parties. What should he do? Six commentators, including a mentor-protégé pair, offer their advice in this fictional case study.

Premenopausal bone mineral content relates to height, weight and calcium intake during early adulthood.

The influence of dietary and anthropometric factors on bone mineral content was studied in 183 healthy premenopausal French-Canadian women aged between 40 and 50 years and living in the same area. Dietary evaluation of their calcium (Ca), caffeine and alcohol intake since the age of 20 was performed in all cases. Age, height, weight, exercise level, cigarette smoking, parity and estrogen were also recorded. Bone mineral content of the L2 to L4 vertebrae (BMCL, n = 183) and forearm (BMCF, n = 137) were measured respectively by dual and single photon absorptiometry. While stepwise regression analysis showed a significant relationship between total BMCL and height, weight and Ca intake, this only occurred with weight and Ca intake when BMCL was corrected for height of L2-L4 (BMCL/cm) or for bone scan area of L2-L4 (BMCL/cm2). BMCF expressed per unit of length correlated to height only. When subjects were divided into three groups according to their Ca intake (less than 500 mg/day, between 500 and 1000 mg/day and greater than 1000 mg/day), the mean BMC adjusted for significant covariables (height and weight) was statistically different for the low and high intake groups at both sites (BMCF, F = 3.9, P = 0.02; BMCL, F = 4.2, P less than 0.02; BMCL/cm, F = 6.1, P less than 0.005; BMCL/cm2, F = 4.4, P less than 0.02). These findings indicate that, of the variables considered, Ca intake, height and weight were the only significant factors related to bone mass in our homogeneous population. It is therefore suggested that Ca intake in early adulthood influences the axial and appendicular bone mass in premenopausal women.

Inhibition of liver regeneration by chronic alcohol administration.

Liver regeneration is the common mechanism whereby a patient recovers form a liver injury. In the western world, ethanol is the single most important aetiological factor associated with liver disease, and it appears crucial to determine if ethanol interferes with liver regeneration. We studied the response to a 70% hepatectomy in 240 rats receiving a nutritionally adequate diet containing 36% of their calories as ethanol for three weeks and their pair-fed controls receiving a liquid diet where ethanol is isocalorically replace with carbohydrates. Criteria of liver regeneration were: incorporation of 3H-thymidine in hepatocyte DNA (cpm/10 microgram DNA) and number of hepatocyte labelled nuclei on autoradiography per 100 high power fields. Controls displayed the usual response with peak activity of liver regeneration at 24 hours. Consumption of ethanol was associated with a statistically significant reduction of liver regeneration by both criteria for up to 72 hours after a 70% hepatectomy and delayed the peak of regenerative activity by 24 hours. This inhibiting effect was not related to the presence of alcohol in blood nor to hepatic microsomal enzyme induction by ethanol nor to widespread necrosis of hepatocytes. This effect was reversible after one week of abstinence. This impairment of liver cell renewal by ethanol may be of major significance in the severity and outcome of alcohol-related liver injury.