Role of Mesenchymal Stem/Stromal Cells (MSCs) and MSC-Derived Extracellular Vesicles (EVs) in Prevention of Telomere Length Shortening, Cellular Senescence, and Accelerated Biological Aging.

Biological aging is defined as a progressive decline in tissue function that eventually results in cell death. Accelerated biologic aging results when the telomere length is shortened prematurely secondary to damage from biological or environmental stressors, leading to a defective reparative mechanism. Stem cells therapy may have a potential role in influencing (counteract/ameliorate) biological aging and maintaining the function of the organism. Mesenchymal stem cells, also called mesenchymal stromal cells (MSCs) are multipotent stem cells of mesodermal origin that can differentiate into other types of cells, such as adipocytes, chondrocytes, and osteocytes. MSCs influence resident cells through the secretion of paracrine bioactive components such as cytokines and extracellular vesicles (EVs). This review examines the changes in telomere length, cellular senescence, and normal biological age, as well as the factors contributing to telomere shortening and accelerated biological aging. The role of MSCs-especially those derived from gestational tissues-in prevention of telomere shortening (TS) and accelerated biological aging is explored. In addition, the strategies to prevent MSC senescence and improve the antiaging therapeutic application of MSCs and MSC-derived EVs in influencing telomere length and cellular senescence are reviewed.

Cord Blood Plasma and Placental Mesenchymal Stem Cells-Derived Exosomes Increase Ex Vivo Expansion of Human Cord Blood Hematopoietic Stem Cells While Maintaining Their Stemness.

BACKGROUND: Mesenchymal stem cells (MSCs) have been used for ex vivo expansion of umbilical cord blood (UCB) hematopoietic stem cells (HSCs) to maintain their primitive characters and long-term reconstitution abilities during transplantation. Therapeutic effects of MSCs mainly rely on paracrine mechanisms, including secretion of exosomes (Exos). The objective of this study was to examine the effect of cord blood plasma (CBP)-derived Exos (CBP Exos) and Placental MSCs-derived Exos (MSCs Exos) on the expansion of UCB HSCs to increase their numbers and keep their primitive characteristics. METHODS: CD34+ cells were isolated from UCB, cultured for 10 days, and the expanded HSCs were sub-cultured in semisolid methylcellulose media for primitive colony forming units (CFUs) assay. MSCs were cultured from placental chorionic plates. RESULTS: CBP Exos and MSCs Exos compared with the control group significantly increased the number of total nucleated cells (TNCs), invitro expansion of CD34+ cells, primitive subpopulations of CD34+38+ and CD34+38-Lin- cells (p < 0.001). The expanded cells showed a significantly higher number of total CFUs in the Exos groups (p < 0.01). CONCLUSION: CBP- and placental-derived exosomes are associated with significant ex vivo expansion of UCB HSCs, while maintaining their primitive characters and may eliminate the need for transplantation of an additional unit of UCB.

Association of saponin concentration, molecular markers, and biochemical factors with enhancing resistance to alfalfa seedling damping-off.

Fifteen alfalfa populations were tested for resistance to the seedling damping-off disease sourced by Rhizoctonia solani, Fusarium solani, and Macrophomina phaseolina. In a laboratory experiment, saponin treatment significantly diminished the mycelial growth of the causal fungi of alfalfa damping-off disease. Roots of the fifteen alfalfa populations varied in saponin and lignin content. Selection for the considerably resistant plants leads to the best growth performance, desirable yield, and high nutritive values such as crude protein (CP), crude fier (CF), nitrogen free extract (NFE), ash, and ether extract (EE) contents. For the PCR reaction, 10 SSR pairs of the JESPR series primers and the cDNA-SCoT technique with seven primers were used. SSR and SCoT revealed some unique markers that could be linked to resistance to damping-off disease in alfalfa that appeared in the considerably resistant alfalfa population (the promised pop.). SSR and SCoT markers can be an excellent molecular method for judging genetic diversity and germplasm classification in tetraploid alfalfa. We recommend breeding for saponin concentration in the alfalfa plant may affect resistance to some diseases like root rot and damping-off because saponin might improve plant growth, yield, and nutritional values.

Stem-Cell Therapy for Bronchopulmonary Dysplasia (BPD) in Newborns.

Premature newborns are at a higher risk for the development of respiratory distress syndrome (RDS), acute lung injury (ALI) associated with lung inflammation, disruption of alveolar structure, impaired alveolar growth, lung fibrosis, impaired lung angiogenesis, and development of bronchopulmonary dysplasia (BPD) with severe long-term developmental adverse effects. The current therapy for BPD is limited to supportive care including high-oxygen therapy and pharmacotherapy. Recognizing more feasible treatment options to improve lung health and reduce complications associated with BPD is essential for improving the overall quality of life of premature infants. There is a reduction in the resident stem cells in lungs of premature infants with BPD, which strongly suggests a critical role of stem cells in BPD pathogenesis; this warrants the exploration of the potential therapeutic use of stem-cell therapy. Stem-cell-based therapies have shown promise for the treatment of many pathological conditions including acute lung injury and BPD. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) including exosomes are promising and effective therapeutic modalities for the treatment of BPD. Treatment with MSCs and EVs may help to reduce lung inflammation, improve pulmonary architecture, attenuate pulmonary fibrosis, and increase the survival rate.

Altered thymocyte and T cell development in neonatal mice with hyperoxia-induced lung injury.

BACKGROUND: The adaptive immune system of neonates is relatively underdeveloped. The thymus is an essential organ for adaptive T cell development and might be affected during the natural course of oxygen induced lung injury. The effect of prolonged hyperoxia on the thymus, thymocyte and T cell development, and its proliferation has not been studied extensively. METHODS: Neonatal mice were exposed to 85% oxygen (hyperoxia) or room air (normoxia) up to 28 days. Flow cytometry using surface markers were used to assay for thymocyte development and proliferation. RESULTS: Mice exposed to prolonged hyperoxia had evidence of lung injury associated alveolar simplification, a significantly lower mean weight, smaller thymic size, lower mean thymocyte count and higher percentage of apoptotic thymocytes. T cells subpopulation in the thymus showed a significant reduction in the count and proliferation of double positive and double negative T cells. There was a significant reduction in the count and proliferation of single positive CD4+ and CD8+ T cells. CONCLUSIONS: Prolonged hyperoxia in neonatal mice adversely affected thymic size, thymocyte count and altered the distribution of T cells sub-populations. These results are consistent with the hypothesis that prolonged hyperoxia causes defective development of T cells in the thymus.

Frontofacionasal Dysplasia in a Newborn with a De Novo Duplication of 7p15.2-p15.1.

We report a new case of frontofacionasal dysplasia or dysostosis (FFND) with a 1.5 Mb duplication in the region of 7p15.2-p15.1, and provide a review of the literature to understand the underlying pathogenesis better.

Two cases of pontocerebellar hypoplasia: ethical and prenatal diagnostic dilemma.

We report the clinical characteristics and the outcome of two cases of pontocerebellar hypoplasia (PCH) in one family. The objective of this report is to describe the mode of presentation, discuss the clinical course, and address the dilemma of prenatal diagnosis and the prospects for genetic diagnosis for PCH. The first case is a 4-year-old boy in whom the diagnosis was made in the neonatal period. Despite extensive prenatal follow-up during the mother's subsequent pregnancy, prenatal diagnosis could not be made and a second affected child was born. Both siblings have severe developmental delay. The cases raise an important ethical dilemma about the most appropriate intervention if the mother of a child affected with PCH becomes pregnant. PCH is considered to have an autosomal-recessive mode of inheritance and a recurrence risk of 25% in each pregnancy. Until recently when genetic mutations in PCH types 2, 4, and 6 began to be identified, the lack of well-recognized genetic testing precluded experts from making clear recommendations. The best advice to these parents was difficult or elusive. With two children currently affected, should the parents terminate or continue with the latest pregnancy? Extensive monitoring with serial prenatal ultrasound failed in the previous pregnancy and resulted in the birth of the second affected child. It is evident that serial ultrasound scan may not be helpful in making the diagnosis prenatally. Therefore, other diagnostic modalities such as magnetic resonance imaging may be necessary and should be considered. With the identification of genetic basis or mutations in PCH types 2, 4, and 6 and possible development of commercial genetic testing for these types of PCH, reproductive decision or genetic testing during pregnancy should be recommended to affected families to enable informed choices.

Outcome of extremely low birth weight infants with leukemoid reaction.

BACKGROUND: Leukemoid reaction (LR) is defined as an absolute neutrophil count (ANC) of >30 x 10(3)/mm(3). No previous study has systemically examined the clinical and prognostic significance of this phenomenon in extremely low birth weight (ELBW) infants. OBJECTIVE: The purpose of this study was to examine the effect of LR in morbidity, mortality, and long-term developmental outcome in ELBW infants. METHOD: Infants with gestational age of 30 x 10(3)/mm(3). RESULTS: LR was detected in 17% of the study infants (26 of 152). ANC increased postnatally in LR (n = 26) and no-LR (n = 126) infants during hospitalization, peaked in the second week of life (43 +/- 3 vs 14 +/- 1 x 10(3)/mm(3)), and remained significantly higher in LR infants during the first 5 weeks of life. LR occurred more frequently during the first 2 weeks of life and lasted for 3 +/- 1 days. There was no significant difference between the LR and no-LR infants in gestational age, birth weight, delivery mode, gender, Apgar scores, or incidence of respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, and retinopathy of prematurity. LR infants required a significantly longer duration of ventilatory support (36 +/- 4 vs 21 +/- 2 days), longer duration of oxygen requirement (58 +/- 6 vs 40 +/- 3 days), and had a higher incidence of bronchopulmonary dysplasia (BPD) (54% vs 25%) compared with no-LR infants. Furthermore, the length of hospitalization was significantly longer in LR infants (69 +/- 6 vs 54 +/- 3 days). There was no significant difference between the groups in developmental outcome at 2 years of age including receptive/expressive language, fine/gross motor skills, and hearing. Incidence of abnormal neurodevelopment outcome was also similar between LR and no-LR infants. CONCLUSIONS: LR in ELBW infants is associated with a prolonged need for ventilatory and oxygen support, a higher incidence of BPD, and a tendency for lower mortality. The findings from our study suggest that LR is associated with conditions known to have an excess of proinflammatory cytokines. Additional prospective study is needed to understand the relationship between LR, proinflammatory cytokines, and development of BPD.

Effects of fluid and electrolyte management on amphotericin B-induced nephrotoxicity among extremely low birth weight infants.

OBJECTIVE: Greater use of invasive procedures and aggressive antimicrobial therapy predispose extremely low birth weight (ELBW) infants to systemic fungal sepsis. Despite its adverse effects (including renal and electrolyte disturbances), amphotericin B (amphoB) remains the preferred drug for fungal therapy. Multiple studies have indicated that sodium loading may prevent renal toxicity among animals and human adults. The effects of fluid and electrolyte management on amphoB-induced nephrotoxicity among ELBW infants have not been evaluated extensively. The purpose of this study was to examine the effects of fluid and electrolyte management on amphoB-induced nephrotoxicity among ELBW infants. DESIGN/METHODS: The medical records were reviewed for all ELBW infants (birth weights of < or =1250 g) who developed systemic fungal sepsis, requiring amphoB therapy, between January 1992 and December 2000. Demographic, clinical, and laboratory data were collected from the medical records for each patient. RESULTS: Fungal sepsis requiring amphoB treatment developed for 4.4% of ELBW infants (25 of 573 infants), with a gestational age of 25 +/- 1 weeks and a birth weight of 738 +/- 37 g, at a postnatal age of 16 +/- 2 days. Renal compromise, as manifested by low urine output and high creatinine levels, occurred for 44% of those infants (11 of 25 infants). There was no difference between the infants who developed renal compromise (renal compromise group [RCG], n = 11) and those who did not (no-renal-compromise group [NCG], n = 14) with respect to birth weight, gestational age, and risk factors predisposing the infants to fungal sepsis. The RCG demonstrated a decrease in urine output by 3.4 +/- 2 days and an increase in serum creatinine levels by 3.9 +/- 2 days after the initiation of amphoB therapy. Infants in the RCG had a significantly higher incidence of hyponatremia, compared with infants in the NCG (7 of 11 infants vs 0 of 14 infants), with no significant difference in the incidences of hypokalemia (2 of 11 infants vs 0 of 14 infants). Infants in the RCG, compared with infants in the NCG, had significantly lower mean daily sodium intakes in the 4 days before the initiation of amphoB therapy (2.6-2.9 mEq/kg per day vs 4.2-4.7 mEq/kg per day) and in the first 4 days of amphoB treatment (2.7-3.1 mEq/kg per day vs 4.5-5.6 mEq/kg per day). Mean daily sodium intakes were not statistically significantly different between the 2 groups between day 5 and day 10 of amphoB therapy. Infants in the RCG tended to have lower mean daily potassium intakes in the 4 days before the initiation of amphoB therapy and during the first 4 days of amphoB therapy. Subsequently, the mean daily potassium intakes remained not statistically significantly different between the groups. Mean daily fluid intakes were not different between the groups. CONCLUSIONS: Conventional amphoB combined with adequate hydration and higher sodium intakes of >4 mEq/kg per day may provide effective protection against amphoB-induced nephrotoxicity among ELBW infants. Our data confirm the published results of animal and human adult studies and suggest that higher sodium intakes may prevent renal compromise during amphoB therapy among ELBW infants.