- Texas H.B. 810: Increased Access to Stem Cell Interventions or an Increase in Unproven Treatments? [Journal Article]
- SCStem Cells Dev 2018 Aug 18
- Born of the expectations and hype associated with regenerative medicine, there are now numerous clinics around the world selling stem cell-based interventions (SCBI) that have yet to be proven effect...
Born of the expectations and hype associated with regenerative medicine, there are now numerous clinics around the world selling stem cell-based interventions (SCBI) that have yet to be proven effective or safe, with little to no accounting of the outcomes being collected. In the US, SCBI are overseen by the US Food and Drug Administration (FDA), but several SCBI clinics have been pushing for policies to expand access and circumvent FDA oversight. Related to this effort, in 2017 Texas passed a bill, HB 810, that allows clinics to provide "investigational stem cell treatments to patients with certain severe chronic diseases or terminal illnesses." In this paper, we describe how the new law relates to another deregulation movement, state and federal the Right to Try laws, the content of HB 810, and the state legislators' intent in passing HB 810.
- Cancer Stem Cells or Tumor Survival Cells? [Journal Article]
- SCStem Cells Dev 2018 Aug 09
- Research endeavors originally generated stem cell definitions for the purpose of describing normally sustainable developmental and tissue turnover processes in various species including humans. The n...
Research endeavors originally generated stem cell definitions for the purpose of describing normally sustainable developmental and tissue turnover processes in various species including humans. The notion of investigating cells that possess a vague capacity of "stamm (phylum)" can be traced back to the late 19th century, mainly concentrating on cells that could produce the germline or the entire blood system. Lately, such undertakings have been recapitulated for oncogenesis, tumor growth and cancer cell resistance to oncolytic therapies. However, due to the complexity and basic life-origin mechanisms comprising the genetic and epigenetic repertoire of the stemness in every developing or growing cell, presently there are ongoing debates regarding the biological essentials of the stem cell-like tumor initiation cells (i.e., cancer stem cells: CSCs). This conceptual analysis focuses on the potential pitfalls of extrapolating that CSCs bear major traits of stemness. We propose a novel nomenclature of Tumor Survival Cells (TSCs) to further define tumor cells behaving like CSCs, based on the ruthless and detrimental features of Cancer Cell Survivology that appears fundamentally different from stem cell biology. Hence, precise academic separation of TSCs from all the stem cell-related labels applied to these unique tumor cells may help to improve scientific reasoning and strategies to decode the desperado-like survival behaviors (DSB) of TSCs in order to eventually overcome cancer.
- Knockdown of p66Shc alters lineage-associated transcription factor expression in mouse blastocysts. [Journal Article]
- SCStem Cells Dev 2018 Aug 09
- The p66Shc adaptor protein regulates apoptosis and senescence during early mammalian development. However, p66Shc expression during mouse preimplantation development is upregulated at the blastocyst ...
The p66Shc adaptor protein regulates apoptosis and senescence during early mammalian development. However, p66Shc expression during mouse preimplantation development is upregulated at the blastocyst stage. Our objective was to determine the biological function of p66Shc during mouse blastocyst development. Here we demonstrate that a reduced p66Shc transcript abundance following its siRNA-mediated knockdown alters the spatiotemporal expression of cell lineage-associated transcription factors in the inner cell mass of the mouse blastocyst. P66Shc knockdown blastocysts restrict OCT3/4 earlier to the inner cells of the early blastocyst and have inner cell masses containing significantly higher OCT3/4 levels, more GATA4-positive cells, and fewer NANOG-positive cells. P66Shc knockdown blastocysts also show a significantly reduced ability to form inner cell mass-derived outgrowths when explanted in vitro. The increase in cells expressing primitive endoderm markers may be due to increased ERK1/2 activity, as it is reversed by ERK1/2 inhibition. These results suggest that p66Shc may regulate the relative abundance and timing of lineage-associated transcription factor expression in the blastocyst inner cell mass.
- TGFBI expressed by bone marrow niche cells and hematopoietic stem and progenitor cells regulates hematopoiesis. [Journal Article]
- SCStem Cells Dev 2018 Aug 07
- The interactions of hematopoietic stem- and progenitor cells (HSPCs) with extracellular matrix components and cells from the bone marrow microenvironment control their homeostasis. Regenerative bone ...
The interactions of hematopoietic stem- and progenitor cells (HSPCs) with extracellular matrix components and cells from the bone marrow microenvironment control their homeostasis. Regenerative bone marrow conditions can induce expression of the extracellular matrix protein transforming growth factor beta induced gene H3 (TGFBI or BIGH3) in murine HSPCs. Here we examined how increased or reduced TGFBI expression in human HSPCs and bone marrow mesenchymal stromal cells (MSCs) affects HSPC maintenance, differentiation and migration. HSPCs that overexpressed TGFBI showed accelerated megakaryopoiesis, whereas granulocyte differentiation and proliferation of granulocyte, erythrocyte and monocyte cultures was reduced. In addition, both up- and downregulation of TGFBI expression impaired HSPC colony forming capacity of HSPCs. Interestingly, the colony forming capacity of HSPCs with reduced TGFBI levels was increased after long term co-culture with MSCs, as measured by long-term-culture-colony-forming-cell (LTC-CFC) formation. Moreover, TGFBI downregulation in HSPCs resulted in increased cobblestone-area-forming cell (CAFC) frequency, a measure for hematopoietic stem cell capacity. Concordantly, TGFBI upregulation in HSPCs resulted in a decrease of CAFC and LTC-CFC frequency. These results indicate that reduced TGFBI levels in HSPCs enhanced HSC maintenance, but only in the presence of MSCs. In addition, reduced levels of TGFBI in MSCs affected MSC/HSPC interaction, as observed by an increased migration of HSPCs under the stromal layer. In conclusion, tight regulation of TGFBI expression in the bone marrow niche is essential for balanced HSPC proliferation and differentiation.
- Novel Insights into Adult and Cancer Stem Cells Biology. [Journal Article]
- SCStem Cells Dev 2018 Jul 27
- Adult tissues are thought to harbor two populations of 'dormant' and 'actively dividing' stem cells. Quiescent stem cells undergo rare asymmetric cell divisions (ACD) whereby they self-renew and give...
Adult tissues are thought to harbor two populations of 'dormant' and 'actively dividing' stem cells. Quiescent stem cells undergo rare asymmetric cell divisions (ACD) whereby they self-renew and give rise to tissue committed 'progenitors' of distinct fate and 'progenitors' in turn undergo symmetric cell divisions (SCD) and clonal expansion. However, quiescent stem cells have not been demonstrated in adult tissues like skin, testis, liver, brain etc. After surgical removal of part of liver and pancreas -adult differentiated cells divide and regenerate and a possible role of stem cells remains doubtful. Long-term repopulating hematopoietic stem cells are quiescent in nature but ACD has not been convincingly demonstrated even amongst them. Attempts by various groups to identify a common stemness program that ensures self-renewal amongst different kinds of stem cells have also remained futile. Uncontrolled self-renewal and compromised differentiation of stem cells possibly initiate leukemia/cancer but the identity of leukemic stem cells and whether cancer stem cells arise by epithelial-mesenchymal transition (EMT) in solid tumors are all open-ended questions that need greater clarity. Acceptance of the presence of very small embryonic-like stem cells (VSELs) in adult tissues could clarify several of these existing dilemmas in the field. Data is compiled showing that VSELs undergo ACD in the hematopoietic system, testis, ovary, uterus and pancreas whereas tissue-committed progenitors undergo SCD and clonal expansion. VSELs possess similar overlapping stemness program as in embryonic stem cells, embryonic carcinoma cells, embryonic germ cells, induced pluripotent stem cells and primordial germ cells. VSELs, leukemic and cancer cells express overlapping embryonic markers. Uncontrolled proliferation of VSELs and compromised differentiation possibly initiates leukemia. Process of EMT and initiation of solid tumor from VSELs (located amongst the epithelial cells) are indeed two distinct and parallel events. To conclude, VSELs provide explanation to several confounding aspects of adult stem cells biology.
- Comparison of antibacterial and immunological properties of Mesenchymal Stem/Stromal cells from equine Bone Marrow, Endometrium and Adipose tissue. [Journal Article]
- SCStem Cells Dev 2018 Jul 25
- Equine Mesenchymal stem/stromal cells (MSCs) are multipotent cells that are widely used for treatment of musculoskeletal injuries, and there is significant interest in expanding their application to ...
Equine Mesenchymal stem/stromal cells (MSCs) are multipotent cells that are widely used for treatment of musculoskeletal injuries, and there is significant interest in expanding their application to non-orthopedic conditions. MSCs possess antibacterial and immunomodulatory properties which may be relevant for combatting infection, however, comparative studies using MSCs from different origins have not been carried out in the horse, and this was the focus of the present study. Our results showed that MSC-conditioned media attenuated the growth of Escherichia coli, and that this effect was, on average, more pronounced for endometrium (EM)- and adipose tissue (AT)- than for bone marrow (BM)-derived MSCs. In addition, the antimicrobial Lipocalin-2 was expressed at mean higher levels in EM- compared to AT- and BM-MSCs, and the bacterial product lipopolysaccharide (LPS) stimulated its production by all three MSC types. We also show that MSCs express IL-6, IL-8, MCP-1, CCL5 and TLR4, and that, in general, these cytokines were induced in all cell types by LPS. Low expression levels of the macrophage marker CSF1-R were detected in BM- and EM-MSCs, but not in AT-MSCs. Altogether, these findings suggest that equine MSCs from endometrium, adipose tissue and bone marrow have both direct and indirect antimicrobial properties which may vary between MSCs from different origins and could be exploited towards improvement of regenerative therapies for horses.
- p53 is active in human amniotic fluid stem cells. [Journal Article]
- SCStem Cells Dev 2018 Jul 25
- Despite increasing interest in human amniotic fluid cells, very little is known about the regulation and function of p53 in this cell type. Here we show that undifferentiated human amniotic fluid cel...
Despite increasing interest in human amniotic fluid cells, very little is known about the regulation and function of p53 in this cell type. Here we show that undifferentiated human amniotic fluid cells express p53 yet at lower levels than in cancer cells. The p53 protein in amniotic fluid cells is mainly localized in the nucleus however its anti-proliferative activity is compromised in these cells. Igf2, a maternal imprinted gene and c-jun, a proto-oncogene, are regulated by p53 in these cells. DNA damage leads to an increase in p53 abundance in human amniotic fluid cells and to transcriptional activation of its target genes. Interestingly, cell differentiation towards the neural lineage leads to p53 induction as differentiation progresses.
- Inhibition of retinoic acid production expands a megakaryocyte-enriched subpopulation with islet supportive function. [Journal Article]
- SCStem Cells Dev 2018 Jul 24
- Islet regeneration is stimulated after transplantation of human umbilical cord blood (UCB) hematopoietic progenitor cells with high ALDH-activity into NOD/SCID mice with streptozotocin-induced β-cell...
Islet regeneration is stimulated after transplantation of human umbilical cord blood (UCB) hematopoietic progenitor cells with high ALDH-activity into NOD/SCID mice with streptozotocin-induced β-cell ablation. ALDHhi progenitor cells represent a rare subset within UCB that will require expansion without the loss of islet regenerative functions for use in cell therapies. ALDHhi cells efficiently expand (>70-fold) under serum-free conditions; however, high ALDH-activity is rapidly diminished during culture coinciding with emergence of a committed megakaryocyte phenotype CD41+/CD42+/CD38+. ALDH-activity is also the rate-limiting step in retinoic acid production, a potent driver of hematopoietic differentiation. We have previously shown that inhibition of retinoic acid production during 9-day cultures, using diethylaminobenzaldehyde (DEAB) treatment, enhanced the expansion of ALDHhi cells (>20-fold) with vascular regenerative paracrine functions. Herein, we sought to determine if DEAB-treatment also expanded ALDHhi cells that retain islet regenerative function following intrapancreatic transplantation into hyperglycemic mice. After DEAB-treatment, expanded ALDHhi cell subset was enriched for CD34+/CD38- expression and demonstrated enhanced myeloid multipotency in vitro compared to the ALDHlo cell subset. Unfortunately, DEAB-treated ALDHhi cells did not support islet regeneration after transplantation. Conversely, expanded ALDHlo cells from DEAB-treated conditions reduced hyperglycemia, and increased islet number and cell proliferation in streptozotocin-induced hyperglycemic NOD/SCID mice. DEAB-treated ALDHlo cells were largely committed to a CD41+/CD42+ megakaryocyte phenotype. Collectively, this study provides preliminary evidence that committed cells of the megakaryocyte-lineage support endogenous islet regeneration and/or function, and the retention of high ALDH-activity did not coincide with islet regenerative function after expansion under serum-free culture conditions.
- Mesenchymal Stromal Cell Preconditioning: The Next Step Towards a Customized Treatment For Severe Burn. [Journal Article]
- SCStem Cells Dev 2018 Jul 24
- Over the last century, the clinical management of severe skin burns significantly progressed with the development of burn care units, topical antimicrobials, resuscitation methods, early eschar excis...
Over the last century, the clinical management of severe skin burns significantly progressed with the development of burn care units, topical antimicrobials, resuscitation methods, early eschar excision surgeries and skin grafts. In spite of these considerable advances, the present treatment of severe burns remains burdensome and patients are highly susceptible to skin engraftment failure, infections, organ dysfunction, and hypertrophic scarring. Recent researches have focused on Mesenchymal Stromal Cell (MSC) therapy and hold great promises for tissue repair, as reported in several animal studies and clinical cases. In the present review, we will provide an up-to-date outlook of the pathophysiology of severe skin burns, clinical treatment modalities and current limitations. We will then focus on MSCs and their potential in the burn wound healing both in in vitro and in vivo studies. A specific attention will be paid to the cell preconditioning approach, as a means of improving the MSC efficacy in the treatment of major skin burns. In particular, we will debate how several preconditioning cues would modulate the MSC properties to better match up with the burn pathophysiology in the course of the cell therapy. Lastly, we will discuss the clinical interest and feasibility of a MSC-based therapy in comparison to their paracrine derivatives including microvesicles and conditioned media for the treatment of major skin burn injuries.
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- The Effects of Ihh deletion on Mesenchyme cells: inducing intermediate cartilage scaffold ossification to cause growth plate and phalange joint absence, short limb, and dwarfish phenotypes. [Journal Article]
- SCStem Cells Dev 2018 Jul 21
- The endochondral ossification plays a critical role in vertebrate limb development and skeletal homeostasis, where limb mesenchyme cells form an intermediate cartilage scaffold that develop into grow...
The endochondral ossification plays a critical role in vertebrate limb development and skeletal homeostasis, where limb mesenchyme cells form an intermediate cartilage scaffold that develop into growth plates and then replaced by bone. Although Indian hedgehog (Ihh) is known to control hypertrophic differentiation process of chondrocytes, its role from the mesenchyme cells to the early stages of chondrogenesis is unclear. To define the function of Ihh in the mesenchymal cell's early stages of chondrogenesis, we specifically delete Ihh in Prx1 expressed mesenchyme cells at E9.5 using Prx1-Cre;Ihh<sup>fl/fl</sup>;Rosa26<sup>-ZsGreen1</sup> mice. We found that deleting Ihh in the mesenchyme cells results in an early and quick ossification of the intermediate cartilage scaffold; causing the growth plate and phalange joint absence, short limbs, and dwarfishness. The GFP positive cells that were derived from deleted Ihh mesenchyme cells overlap with von Kassa and Osteocalcin positive staining area. These deleted Ihh/GFP positive cells isolated from Prx1-Cre;Ihh<sup>fl/fl</sup>;Rosa26<sup>-ZsGreen1 </sup>new born mice had osteogenic differentiation by showing a positive Alizarin red and von Kossa staining, as well as an enhanced Col1a1, Osteocalcin, Runx2 expression. Our findings demonstrate that deleting Ihh in mesenchyme cells during early limb development promote intermediate cartilage scaffold ossification, which prevents growth plate formation that causes phalange joint absence, short limb, and dwarfish phenotype.