Aurochs, genetics, indigenous people and colonists: apropos of the neolithization of Europe

Las analíticas genéticas realizadas sobre los uros (Bos primigenius) del yacimiento de Mendandia (Treviño), han ofrecido un resultado sorprendente: uno de los individuos pertenece al haplotypo T3, generalmente asociado a animales domésticos (Bos taurus). La datación de la muestra (7265 ± 70 BP; Ua 34366) es acorde con las otras conocidas de su nivel, el III-superior, incidiendo en la antigüedad de su Neolítico. El dato es la excusa para reflexionar sobre el proceso neolitizador y adentrarnos en el debate sobre el papel que pudiera corresponder a los indígenas y a los colonos. Para ello se valora la información más actual sobre genética de las poblaciones del principio del Holoceno, las medias promediadas de la extensión por Europa del nuevo modo de vida, así como otros indicios de neolitización prematura. Un compendio de razones que nos lleva a pensar que estamos frente a un fenómeno cultural muy complejo

Maternal and fetal safety outcomes after in utero stem cell injection: A systematic review

Objective: To investigate the maternal and fetal safety of In utero stem cell transplantation (IUSCT). Methods: Medline®, Embase and Cochrane library (1967−2023) search for publications reporting IUSCT in humans. Two reviewers independently screened abstracts and full-text papers. Results: Sixty six transplantation procedures in 52 fetuses were performed for haemoglobinopathies (n = 14), red cell/bleeding disorders (n = 4), immunodeficiencies (n = 15), storage disorders (n = 7), osteogenesis imperfecta (n = 2) and healthy fetuses (n = 10). The average gestational age was 18.9 weeks; of procedures reporting the injection route, cells were delivered by intraperitoneal (n = 37), intravenous (n = 19), or intracardiac (n = 4) injection or a combination (n = 3); most fetuses received one injection (n = 41). Haematopoietic (n = 40) or mesenchymal (n = 12) stem cells were delivered. The cell dose was inconsistently reported (range 1.8−3.3 × 109 cells total (n = 27); 2.7−5.0 × 109/kg estimated fetal weight (n = 17)). The acute fetal procedural complication rate was 4.5% (3/66); the acute fetal mortality rate was 3.0% (2/66). Neonatal survival was 69.2% (36/52). Immediate maternal and pregnancy outcomes were reported in only 30.8% (16/52) and 44.2% (23/52) of cases respectively. Four fetal/pregnancy outcomes would also classify as ≥ Grade 2 maternal adverse events. Conclusions: Short-, medium-, and long-term maternal and fetal adverse events should be reported in all IUSCT studies

Aurochs, genetics, indigenous people and colonists: apropos of the neolithization of Europe

El presente trabajo se ha preparado en el seno de los intereses de los proyectos de investigación: HAR2011-26364 “Las Comunidades humanas de la alta Cuenca del Ebro en la Transición Pleistoceno-Holoceno” del Ministerio de Ciencia e Innovación y CGL2009-12703-C03-03 “Geología, geocronología y paleobiología de los Yacimientos de la Sierra de Atapuerca” del Ministerio de Educación y Ciencia. Así mismo se encuadra en el trabajo del Grupo de Investigación en Prehistoria de la Universidad del País Vasco (UPV/EHU) IT-288-07/ UFI 11-09.[ES] Las analíticas genéticas realizadas sobre los uros (Bos primigenius) del yacimiento de Mendandia (Treviño), han ofrecido un resultado sorprendente: uno de los individuos pertenece al haplotypo T3, generalmente asociado a animales domésticos (Bos taurus). La datación de la muestra (7265 ± 70 BP; Ua 34366) es acorde con las otras conocidas de su nivel, el III-superior, incidiendo en la antigüedad de su Neolítico. El dato es la excusa para reflexionar sobre el proceso neolitizador y adentrarnos en el debate sobre el papel que pudiera corresponder a los indígenas y a los colonos. Para ello se valora la información más actual sobre genética de las poblaciones del principio del Holoceno, las medias promediadas de la extensión por Europa del nuevo modo de vida, así como otros indicios de neolitización prematura. Un compendio de razones que nos lleva a pensar que estamos frente a un fenómeno cultural muy complejo.[EN] The mt-DNA analysis of auroch (Bos primigenius) bones from the site of Mendandia (Treviño), has produced a surprising result: one of the specimens has been identified with the genetic haplotype T3, the most common in European domestic cattle and generally considered unique (and indicative) of domestic livestock (Bos taurus). The direct radiocarbon dating of the sample (7265 ± 70 BP; Ua 34366) is consistent with the older Neolithic age of the level that yielded the sample (Level III-superior). This result is an opportunity to think about the process of Neolitization and enter into the debate about the role that may correspond to the indigenous people and immigrants. We evaluate the latest information on population genetics from the beginning of the Holocene as well as the average extension throughout Europe of early Neolithic settlements and lifestyle. The discussion leads us to believe that we are facing a very complex cultural phenomenon

An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: The BOOSTB4 trial protocol

Introduction Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4. Methods and analysis BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial. Each subject receives four intravenous doses of 3×10 6 /kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally. The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover. Ethics and dissemination The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals. Trial registration numbers EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482

Characterisation of human fetal mesenchymal stem cells

Mesenchymal stem cells (MSCs) are present in various tissues of fetal and adult origin. I isolated and expanded MSCs from human fetal 1st trimester livers and observed that they have a shorter cell doubling time compared to adult bone marrow-derived MSCs. Fetal MSCs differentiated into osteogenic, chondrogenic and adipogenic lineages when induced in vitro. Furthermore, functional assays of adipocyte-differentiated fetal and adult MSCs demonstrated that the intracellular pathways, expression of proteins involved in lipolysis, lipolytic activity and secretion of leptin and adiponectin were similar to that of mature adipocytes, although some differences were noted. Fetal MSCs did not differentiate into adipocytes as readily as adult MSCs did. Fetal MSCs exhibit a similar morphology and surface expression pattern as adult MSCs. Analysis of surface proteins by flow cytometry showed presence of CD29, CD44, CD73, CD105 and CD166 but not of the hematopoietic markers CD34, CD45 or CD14. HLA class I expression was lower in fetal than in adult MSCs. HLA class II could not be detected on the surface, and fetal MSCs had no intracellular deposits of HLA class II as did adult MSCs. Seven days of IFNgamma exposure was required for full surface expression of HLA class II, compared to two days for adult MSCs. Fetal MSCs, like adult MSCs, did not upregulate HLA class II during differentiation to osteogenic, chondrogenic and adipogenic lineages. Further analysis of differences between fetal and adult MSCs was conducted by gene array. Transcriptomes of fetal and adult MSCs differed mainly in genes coding for developmental, cell cycle regulatory and immunologic transcripts. Fetal MSCs showed increased expression of transcripts involved in germ plasm and limb patterning and in brain and early muscle development. The expression of transcripts implicated in cell cycle promotion, chromatin regulation and DNA repair were also more abundant in fetal MSCs. Transcripts with reduced expression in comparison to adult MSCs were those involved in smooth muscle and keratinocyte differentiation. Fetal MSCs expressed fewer transcripts for immunologic genes, which could imply that fetal MSCs are less immunologically mature than adult MSCs. The effect of fetal MSCs on proliferating lymphocytes was investigated by co-culture experiments and mitogen assays. Mitogen stimulation of lymphocytes was inhibited by fetal MSCs. Neither undifferentiated nor differentiated fetal MSC induced proliferation of allogeneic lymphocytes. Unlike adult MSCs, fetal MSCs did not inhibit proliferating lymphocytes, while fetal MSCs treated with IFNgamma for seven days did. These results suggest that fetal MSCs are immunologically privileged cells and have potentials for allogeneic transplantation. MSCs may be used in cellular therapies. A female fetus with multiple intrauterine fractures, diagnosed as severe osteogenesis imperfecta, was transplanted with HLA-mismatched male fetal MSCs in the 32nd week of gestation. At 35 weeks, the baby girl was delivered by cesarean section. At nine months of age a centromeric XY-specific probe revealed 0.3% of XY-positive cells in a bone marrow biopsy. Whole Y genome FISH staining showed a median of 7.4% Y-positive cells. Patient lymphocyte proliferation against donor MSCs was not observed in co-culture experiments performed in vitro before and after MSC injection, indicating that the patient was not immunised against the allogeneic cells. During the first two years of life three fractures were noted and growth followed the same curve. Thus, allogeneic mis-matched MSCs can be safely transplanted in utero to a patient with severe OI, where the cells engraft in bone. To conclude, fetal MSCs may be a valuable source for transplantation

Mesenchymal Stromal Cells Are More Immunosuppressive In Vitro If They Are Derived from Endometriotic Lesions than from Eutopic Endometrium

Endometriosis is an inflammatory disease with predominance of immunosuppressive M2 macrophages in the pelvic cavity that could be involved in the pathology through support and immune escape of ectopic lesions. Mesenchymal stromal cells (MSC) are found in ectopic lesions, and MSC from nonendometriosis sources are known to induce M2 macrophages. Therefore, MSC were hypothesized to play a role in the pathology of endometriosis. The aim was to characterize the functional phenotype of MSC in ectopic and eutopic endometrium from women with endometriosis. Stromal cells from endometriotic ovarian cysts (ESCcyst) and endometrium (ESCendo) were examined if they exhibited a MSC phenotype. Then, ESC were phenotypically examined for protein and gene expression of immunosuppressive and immunostimulatory molecules. Finally, ESC were functionally examined for their effects on monocyte differentiation into macrophages. ESCcyst and ESCendo expressed MSC markers, formed colonies, and differentiated into osteoblasts and adipocytes. Phenotypically, ESCcyst were more immunosuppressive, with significantly higher expression of immunosuppressive molecules. Functionally, ESCcyst induced more spindle-shaped macrophages, with significantly higher expression of CD14 and CD163, both features of M2 macrophages. The results suggest that ESCcyst may be more immunosuppressive than ESCendo and may promote immunosuppressive M2 macrophages that may support growth and reduce immunosurveillance of ectopic lesions

Soft Tissue Repair with Easy-Accessible Autologous Newborn Placenta or Umbilical Cord Blood in Severe Malformations: A Primary Evaluation

Disrupted organogenesis leads to permanent malformations that may require surgical correction. Autologous tissue grafts may be needed in severe lack of orthotopic tissue but include donor site morbidity. The placenta is commonly discarded after birth and has a therapeutic potential. The aim of this study was to determine if the amnion from placenta or plasma rich of growth factors (PRGF) with mononuclear cells (MNC) from umbilical cord blood (UCB), collected noninvasively, could be used as bio-constructs for autologous transplantation as an easy-accessible no cell culture-required method. Human amnion and PRGF gel were isolated and kept in culture for up to 21 days with or without small intestine submucosa (SIS). The cells in the constructs showed a robust phenotype without induced increased proliferation (Ki67) or apoptosis (caspase 3), but the constructs showed decreased integrity of the amnion-epithelial layer at the end of culture. Amnion-residing cells in the SIS constructs expressed CD73 or pan-cytokeratin, and cells in the PRGF-SIS constructs expressed CD45 and CD34. This study shows that amnion and UCB are potential sources for production of autologous grafts in the correction of congenital soft tissue defects. The constructs can be made promptly after birth with minimal handling or cell expansion needed

Mesenchymal Stromal Cells Support Endometriotic Stromal Cells In Vitro

Endometriosis is an inflammatory disease marked by ectopic growth of endometrial cells. Mesenchymal stromal cells (MSC) have immunosuppressive properties that have been suggested as a treatment for inflammatory diseases. Therefore, the aim herein was to examine effects of allogeneic MSC on endometriosis-derived cells in vitro as a potential therapy for endometriosis. MSC from allogeneic adipose tissue (Ad-MSC) and stromal cells from endometrium (ESCendo) and endometriotic ovarian cysts (ESCcyst) from women with endometriosis were isolated. The effects of Ad-MSC on ESCendo and ESCcyst were investigated using in vitro proliferation, apoptosis, adhesion, tube formation, migration, and invasion assays. Ad-MSC significantly increased proliferation of ESC compared to untreated controls. Moreover, Ad-MSC significantly decreased apoptosis and increased survival of ESC. Ad-MSC significantly increased adhesion of ESCendo and not ESCcyst on fibronectin. Conditioned medium from cocultures of Ad-MSC and ESC significantly increased tube formation of human umbilical vein endothelial cells on matrigel. Ad-MSC may significantly increase migration of ESCcyst and did not increase invasion of both cell types. The data suggest that allogeneic Ad-MSC should not be considered as a potential therapy for endometriosis, because they may support the pathology by maintaining and increasing growth of ectopic endometrial tissue