Hypoxia Modulates Regenerative Potential of Fetal Stem Cells

Adult mesenchymal stem cells (MSCs) are prone to senescence, which limits the scope of their use in tissue engineering and regeneration and increases the likelihood of post-implantation failure. As a robust alternative cell source, fetal stem cells can prevent an immune reaction and senescence. However, few studies use this cell type. In this study, we sought to characterize fetal cells’ regenerative potential in hypoxic conditions. Specifically, we examined whether hypoxic exposure during the expansion and differentiation phases would affect human fetal nucleus pulposus cell (NPC) and fetal synovium-derived stem cell (SDSC) plasticity and three-lineage differentiation potential. We concluded that fetal NPCs represent the most promising cell source for chondrogenic differentiation, as they are more responsive and display stronger phenotypic stability, particularly when expanded and differentiated in hypoxic conditions. Fetal SDSCs have less potential for chondrogenic differentiation compared to their adult counterpart. This study also indicated that fetal SDSCs exhibit a discrepancy in adipogenic and osteogenic differentiation in response to hypoxia.

Age-specific different immune responses due to capabilities of secreting primal immunoglobulins responding to unexperienced antigens

Among numerous studies on COVID-19, we noted that the infection and mortality rates of SARS-CoV-2 increased with age and that fetuses known to be particularly susceptible to infection were better protected despite various mutations. Hence, we established the hypothesis that a new immune system exists that forms before birth and decreases with aging. To prove this, we analyzed the components from early pregnancy fetal stem cells cultivated in various ex-vivo culture conditions simulating the environment during pregnancy. Resultingly, we confirmed that IgM, a natural antibody produced only in early B-1 cells, immunoglobulins including IgG3, which has a wide range of antigen-binding capacity and affinity, complement proteins, and antiviral proteins are induced. Our results suggest that fetal stem cells can form an independent immune system responding to unlearned antigens as a self-defense mechanism before establishing mature immune systems. Moreover, we propose the possibility of new solutions to cope with various infectious diseases based on the factors therein.

Towards a bioengineered uterus: bioactive sheep uterus scaffolds are effectively recellularized by enzymatic preconditioning

Uterine factor infertility was considered incurable until recently when we reported the first successful live birth after uterus transplantation. However, risky donor surgery and immunosuppressive therapy are factors that may be avoided with bioengineering. For example, transplanted recellularized constructs derived from decellularized tissue restored fertility in rodent models and mandate translational studies. In this study, we decellularized whole sheep uterus with three different protocols using 0.5% sodium dodecyl sulfate, 2% sodium deoxycholate (SDC) or 2% SDC, and 1% Triton X-100. Scaffolds were then assessed for bioactivity using the dorsal root ganglion and chorioallantoic membrane assays, and we found that all the uterus scaffolds exhibited growth factor activity that promoted neurogenesis and angiogenesis. Extensive recellularization optimization was conducted using multipotent sheep fetal stem cells and we report results from the following three in vitro conditions; (a) standard cell culturing conditions, (b) constructs cultured in transwells, and (c) scaffolds preconditioned with matrix metalloproteinase 2 and 9. The recellularization efficiency was improved short-term when transwells were used compared with standard culturing conditions. However, the recellularization efficiency in scaffolds preconditioned with matrix metalloproteinases was 200–300% better than the other strategies evaluated herein, independent of decellularization protocol. Hence, a major recellularization hurdle has been overcome with the improved recellularization strategies and in vitro platforms described herein. These results are an important milestone and should facilitate the production of large bioengineered grafts suitable for future in vivo applications in the sheep, which is an essential step before considering these principles in a clinical setting.

Is There an Effect of Fetal Mesenchymal Stem Cells in the Mother–Fetus Dyad in COVID-19 Pregnancies and Vertical Transmission?

Because of the polysystemic nature of coronavirus disease 2019 (COVID-19), during the present pandemic, there have been serious concerns regarding pregnancy, vertical transmission, and intrapartum risk. The majority of pregnant patients with COVID-19 infection present with mild or asymptomatic course of the disease. Some cases were hospitalized, and few needed intensive care unit admission, or mechanical ventilation. There have also been scarce case reports where neonates required mechanical ventilation post COVID-19 pregnancies. Without approved therapies other than dexamethasone, advanced mesenchymal cell therapy is one immunomodulatory therapeutic approach that is currently explored and might hold great promise. We suggest that the circulating fetal stem cells might have an immune-protective effect to mothers and contribute to the often mild and even asymptomatic post-COVID-19 pregnancies. Thus, COVID-19 pregnancies come forth as a paradigm to be further and more comprehensively approached, to understand both the mechanism and action of circulating stem cells in immunoprotection and hypoxia in microcirculation.

Stem Cells: Insights into Niche, Classification, Identification, Characterization, Mechanisms of Regeneration by Using Stem Cells, and Applications in Joint Disease Remedy

Background: Stem cell therapy has attracted much interest in the 21st century, not only because of the controversy surrounding the ethics involving pluripotent stem cells, but their potential for clinical use. Objectives: The present review highlights the stem cells niche, types, identification, and characterization, mechanisms of regeneration by using stem cells, and applications in joint disease remedy. Stem cells could be well differentiated cells with the potential to display different cell types depending on the host niche. Niche is defined as the cellular microenvironment providing support and stimuli to control the properties of stem cells. It consists of signaling molecules, inter-cell contacts and interaction between stem cells and their extracellular matrix neighbors. Stem cells are classified according to their sources into two main types, the embryonic and non-embryonic. Embryonic stem cells are pluripotent and can differentiate into all germ layers. Non-embryonic stem cells can be sub-classified into fetal stem cells and adult stem cells. Cultured cells can be made to differentiate into exclusive lineages by providing selective media components that can be identified by histochemical staining and quantified by quantitative Real-time polymerase chain reaction. Mesenchymal stem cells (MSCs) can be identified based on the expression of specific proteins called surface antigen phenotype of mesenchymal stem cell markers. MSCs secrete a variety of interleukins, several neurotrophic factors, many cytokines, and growth factors. These secreted bioactive factors have both paracrine and autocrine effects, which are anti-fibrotic and anti-apoptotic, as well as enhance angiogenesis. Furthermore, they stimulate mitosis and differentiation of tissue-intrinsic reparative stem cells. Systemic MSC transplantation can engraft to an injured tissue and promote wound healing through differentiation, and proliferation in synergy with hematopoietic stem cells. MSCs have been shown to express a variety of chemokines and chemokine receptors and can home to sites of inflammation by migrating towards injury or inflammatory chemokines and cytokines. MSCs are proven to have immunomodulatory properties that are among the most intriguing aspects of their biology. The immunosuppressive properties of MSCs inhibit the immune response of naive and memory T cells in a mixed lymphocyte culture and induce mitogen. The systemic infusion of MSCs can be used in immunosuppressive therapy of various disorders. MSCs have become an alternative source of cells that can be drawn from several these cells have been used as treatment to repair cartilage defects at early stages sources. Using the MSCs and directing them into chondrogenic differentiation might lead to the formation of higher quality cartilage, which has a great composition of hyaline, adequate structural reorganization and therefore improved biomechanical properties. Conclusion: It can be concluded that stem cells are classified according to their sources into two main types, the embryonic and non-embryonic. Embryonic stem cells are pluripotent and can differentiate into all germ layers. Non-embryonic stem cells can be sub-classified into fetal stem cells and adult stem cells. MSCs secrete bioactive factors that are anti-fibrotic and anti-apoptotic, as well as enhance angiogenesis. The systemic infusion of MSCs can be used in immunosuppressive therapy of various disorders. These cells have been used as treatment to repair cartilage defects at early stages.

Increased Mutagenesis during Fetal Hematopoietic Development in Down Syndrome

Children with Down syndrome are predisposed to leukemia during the first years of their life. 5-10% of newborns with Down syndrome are born with transient myeloproliferative disorder (TMD), which often spontaneously disappears. The majority of these patients achieves complete remission. However, in 20-30% of all TMD patients the disease progress in acute megakaryoblastic leukemia. In addition, they have a 20 fold higher risk of developing B-lymphocyte acute leukemia (B-ALL). Leukemic development in Down syndrome is initiated during fetal development. However, it is unclear why fetuses with a trisomy of chromosome 21 have an increased risk of developing leukemia. Previously, we have developed a method to study somatic mutations in single cells using clonal cultures. Here, we applied this method to human fetal hematopoietic stem and progenitor cells (HSPCs) from liver and bone marrow of Down syndrome human fetuses and control fetuses with two copies of chromosome 21 (D21). In addition, we characterized somatic mutation accumulation in not affected small intestine stem cells. Subsequently, we performed in depth mutational analyses to characterize active processes using mutational signatures in fetal stem cells, which potentially can drive leukemic development during early life. Recently, we have shown that that healthy adult HSPCs gradually accumulate somatic mutations in a linear fashion with an annual mutation rate of 14.2 base substitutions per year. Whereas the somatic mutation rate is significantly higher during fetal development. Subsequently, in Down syndrome fetuses the overall somatic mutation rate of fetal stem cells is significantly increased compared to D21 fetal stem cells (P-value: 0,024). We performed phylogenetic analysis to study relatedness of the cells and observed an higher somatic mutation rate in the first cell divisions. This elevated mutation rate can be explained by increased contribution of mutational process signature 1 and 5, which are already present in fetal stem cells. Therefore, Down syndrome fetal stem cells show enhanced activity or increased sensitivity to mutational processes that are normally active during development. The same mutational signatures are present in TMD blast cells, indicating that these processes can cause cancer driver mutations and subsequently contribute to leukemic development. Interestingly, some Down syndrome fetal stem cells showed very high mutation numbers that could partly be attributed to mutational signature 18, which likely reflect oxidative-stress induced mutagenesis. These findings, show increased mutagenesis in Down syndrome during fetal development in hematopoietic stem cells and small intestine stem cells. This increased mutagenesis can potentially explain why children with Down syndrome have an increased risk of developing leukemia in early life. Disclosures No relevant conflicts of interest to declare.