Cardioprotective Effects of Wharton Jelly Derived Mesenchymal Stem Cell Transplantation in a Rodent Model of Myocardial Injury

BACKGROUND: Whartons jelly-derived mesenchymal stem cells are a valuable alternative source that possess multipotent properties, easy to obtain and available in large scale compared to BMMSCs. We investigated the possibility of cardiac function improvement post isoproterenol induced cardiac injury in a rat model following human WJMSCs transplantation. MATERIALS AND METHODS: MSCs were extracted and cultured from cord WJ, characterized by morphology, Immunophenotyping and differentiation to osteoblast and adipocytes. WJMSCs were labeled with PKH2 linker dye. Wistar rats were divided into control group, ISO group (injected with 2 doses of isoproterenol) to induce myocardial injury and ISO group transplanted with labelled WJMSCs. ECG, electrocardiographic patterns, cardiac marker enzymes, tracing of labeled MSCs and immunohistochemical analysis of myocardial cryosections were studied. RESULTS AND CONCLUSIONS: WJ derived MSCs were expanded for more than 14 passages while maintaining their un-differentiated state, were positive for MSC markers and were able to differentiate into adipocyte and osteoblast. We demonstrated that intravenously administered WJMSCs were capable of homing predominently in the ischemic myocardium. Cardiac markers were positively altered in stem cell treated group compared to ISO group. ECG and ECHO changes were improved with higher survival rate. WJMSCs could differentiate into cardiac-like cells (positive for cardiac specific proteins) in vivo. WJMSCs infusion promoted cardiac protection and reduced mortality, emphasizing a promising therapeutic role for myocardial insufficiency.

Vascular endothelial growth factor [VEGF-C] signaling through KDR [VEGFR-2] and FLT-4 [VEGFR-3] mediates leukemic cell proliferation and survival

VEGF, a key angiogenic molecule, is a multifunctional cytokine that acts both as a potent inducer of vascular permeability and as a specific endothelial cell mitogen. Because of its effects on endothelial cell growth and microvascular permeability, VEGF is believed to be an important mediator of tumor angiogenesis. Leukemic cells not only release VEGF but also express its receptors, resulting in the establishment of an autocrine loop that supports their migration and survival. VEGF-C may play an important role in the pathophysiology of hematopoietic malignancies by not only regulation of lymphangiogenesis, in vivo, but also by promotion of angiogenesis invasion of neoplastic cells into lymphatic vessels and enhancing lymphatic metastasis during tumor progression. although it is well established that growth in solid tumors is dependent on the formation of neovasculature, the role of angiogenesis in hematopoietic neoplasms has not been determined. The present study was undertaken to identify whether VEGF-C and its receptors VEGFR-2 [KDR] and VEGFR-3 [FLT-4] were expressed in patients with denovo acute leukemia by RT-PCR and to evaluate the relationship between their expression and clinical, laboratory findings and prognosis. Using reverse transcription polymerase chain reaction analysis [RT-PCR], 30 de novo acute leukemia patients [20 ALL patients and 10 AML patients] as well as 10 controls were tested for the expressions of VEGF-C, VEGFR-3 [FLT 4] and VEGFR-2 [KDR] genes. In the current study, VEGF-C, FLT-4 and KDR were detected in 10% of control samples. In ALL patients VEGF C was expressed in 65% of cases, FLT-4 in 70% of cases and KDR in 30% of cases. The expressions of VEGF-C, FLT-4 and KDR in ALL patients were associated with increased risk of leukemia [with OR 16.7 and 95% CI 1.7-160.4, OR 21.0 and 95% CI 2.2-204.6 and with OR 3.9 and 95% CI 0.4-37.6 respectively]. In AML patients, VEGF-C was expressed in 60% of cases, FLT-4 in 70% of cases and KDR in 40% of cases. The expression of VEGF-C, FLT-4 and KDR in AML patients was associated with increased risk of leukemia [with OR 13.5 and 95% CI 1.2-152.2, OR 21.0 and 95% CI 1.8-248.1 and OR 6.0 and 95% CI 0.5-67.7 respectively]. In the 6 followed-up ALL patients, 3 [50%] were in remission, three of them were VEGF-C negative, 2 were FLT4 positive and 1 was KDR positive. 2 of the 6 ALL patients [33.3%] were resistant to treatment, both were VEGF-C positive, FLT-4 positive and 1 was KDR positive. One of the 6 ALL patients [16.6% died during induction, this patient was VEGF-C positive and FLT-4 and KDR negative. In the 4 followed-up AML patients, 3 of them [75%] were in remission, 1 of the 3 was VEGF-C positive and 2 were FLT-4 positive. One of the four AML patients [25%] was resistant to treatment, this patient was VEGF-C, FLT-4 and KDR positive. The number of VEGF-C positive patients with no treatment failure was lower than the number of VEGF-C positive patients with treatment failure. Also, the risk of failed induction was found to be greater in VEGF-C positive patients than in VEGF-C negative patients, thus, the expression of VEGF-C and its receptors [FLT-4 and KDR] in ALL and AML patients was associated with increased risk of leukemia and unfavorable treatment outcome. VEGF-C and its receptors KDR [VEGFR-2] and FLT-4 [VEGFR-3] may play an important role in the pathophysiology of hematopoietic malignancies and may actually contribute to the development of leukemia. Also, owing to the importance of angiogenesis in tumor progression and the effects of VEGF-C, KDR and FLT-4 in chemotherapy-treated leukemias, inhibition of VEGF-C signaling represents an attractive cancer treatment