Acta Naturae. 2010 Jul; 2(2): 1828.

Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Research Center of Clinical and Experimental Medicine, Siberian Branch, Russian Academy of Medical Sciences

Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences

Research Center of Clinical and Experimental Medicine, Siberian Branch, Russian Academy of Medical Sciences

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Induced pluripotent stem cells (iPSCs) are a new type of pluripotent cellsthat can be obtained by reprogramming animal and human differentiated cells. In this review,issues related to the nature of iPSCs are discussed and different methods ofiPSC production are described. We particularly focused on methods of iPSC production withoutthe genetic modification of the cell genome and with means for increasing the iPSC productionefficiency. The possibility and issues related to the safety of iPSC use in cell replacementtherapy of human diseases and a study of new medicines are considered.

Keywords: induced pluripotent stem cells, directed stem cell differentiation, cell replacement therapy

Pluripotent stem cells are a unique model for studying a variety of processes that occur inthe early development of mammals and a promising tool in cell therapy of human diseases. Theunique nature of these cells lies in their capability, when cultured, for unlimitedselfrenewal and reproduction of all adult cell types in the course of theirdifferentiation [1]. Pluripotency is supported by acomplex system of signaling molecules and gene network that is specific for pluripotent cells.The pivotal position in the hierarchy of genes implicated in the maintenance of pluripotency isoccupied by Oct4, Sox2 , and Nanog genes encodingtranscription factors [2, 3]. The mutual effect of outer signaling molecules and inner factors leads tothe formation of a specific expression pattern, as well as to the epigenome statecharacteristic of stem cells. Both spontaneous and directed differentiations are associatedwith changes in the expression pattern and massive epigenetic transformations, leading totranscriptome and epigenome adjustment to a distinct cell type.

Until recently, embryonic stem cells (ESCs) were the only wellstudied source ofpluripotent stem cells. ESCs are obtained from either the inner cell mass or epiblast ofblastocysts [46]. A series of protocols has been developed for the preparation of variouscell derivatives from human ESCs. However, there are constraints for ESC usein cell replacement therapy. The first constraint is the immune incompatibility between thedonor cells and the recipient, which can result in the rejection of transplanted cells. Thesecond constraint is ethical, because the embryo dies during the isolation of ESCs. The firstproblem can be solved by the somatic cell nuclear transfer into the egg cell and then obtainingthe embryo and ESCs. The nuclear transfer leads to genome reprogramming, in which ovariancytoplasmic factors are implicated. This way of preparing pluripotent cells from certainindividuals was called therapeutic cloning. However, this method is technologyintensive,and the reprogramming yield is very low. Moreover, this approach encounters theabovementioned ethic problem that, in this case, is associated with the generation ofmany human ovarian cells [7].

In 2006, the preparation of pluripotent cells by the ectopic expression of four genes Oct4 , Sox2 , Klf4 , and cMyc in both embryonic and adult murine fibroblasts was first reported[8]. The pluripotent cells derived from somatic ones werecalled induced pluripotent stem cells (iPSCs). Using this set of factors(Oct4, Sox2, Klf4, and cMyc), iPSCs were prepared later from variousdifferentiated mouse [914] and human [1517] cell types. Human iPSCs were obtainedwith a somewhat altered gene set: Oct4 , Sox2 , Nanog , and Lin28 [18].Induced PSCs closely resemble ESCs in a broad spectrum of features. They possess similarmorphologies and growth manners and are equally sensitive to growth factors and signalingmolecules. Like ESCs, iPSCs can differentiate in vitro intoderivatives of all three primary germ layers (ectoderm, mesoderm, and endoderm) and formteratomas following their subcutaneous injection into immunodeficient mice. MurineiPSCs injected into blastocysts are normally included in the development toyield animals with a high degree of chimerism. Moreover, murine iPSCs, wheninjected into tetraploid blastocycts, can develop into a whole organism [19, 20]. Thus, an excellent method thatallows the preparation of pluripotent stem cells from various somatic cell types whilebypassing ethical problems has been uncovered by researchers.

In the first works on murine and human iPSC production, either retro or lentiviralvectors were used for the delivery of Oct4 , Sox2 , Klf4 , and cMyc genes into somatic cells. Theefficiency of transduction with retroviruses is high enough, although it is not the same fordifferent cell types. Retroviral integration into the host genome requires a comparatively highdivision rate, which is characteristic of the relatively narrow spectrum of cultured cells.Moreover, the transcription of retroviral construct under the control of a promoter localizedin 5LTR (long terminal repeat) is terminated when the somatic celltransform switches to the pluripotent state [21]. Thisfeature makes retroviruses attractive in iPSC production. Nevertheless, retroviruses possesssome properties that make iPSCs that are produced using them improper for celltherapy of human diseases. First, retroviral DNA is integrated into the host cell genome. Theintegration occurs randomly; i.e., there are no specific sequences or apparent logic forretroviral integration. The copy number of the exogenous retroviral DNA that is integrated intoa genome may vary to a great extent [15]. Retrovirusesbeing integrated into the cell genome can introduce promoter elements and polyadenylationsignals; they can also interpose coding sequences, thus affecting transcription. Second, sincethe transcription level of exogenous Oct4 , Sox2 , Klf4 , and cMyc in the retroviral constructdecreases with cell transition into the pluripotent state, this can result in a decrease in theefficiency of the stable iPSC line production, because the switch from the exogenous expressionof pluripotency genes to their endogenous expression may not occur. Third, some studies showthat the transcription of transgenes can resume in the cells derived fromiPSCs [22]. The high probability thatthe ectopic Oct4 , Sox2 , Klf4 , and cMyc gene expression will resume makes it impossible to applyiPSCs produced with the use of retroviruses in clinical trials; moreover,these iPSCs are hardly applicable even for fundamental studies onreprogramming and pluripotency principles. Lentiviruses used for iPSC production can also beintegrated into the genome and maintain their transcriptional activity in pluripotent cells.One way to avoid this situation is to use promoters controlled by exogenous substances added tothe culture medium, such as tetracycline and doxycycline, which allows the transgenetranscription to be regulated. iPSCs are already being produced using suchsystems [23].

Another serious problem is the gene set itself that is used for the induction of pluripotency[22]. The ectopic transcription of Oct4 , Sox2 , Klf4 , and cMyc can lead to neoplastic development from cells derived from iPSCs,because the expression of Oct4 , Sox2 , Klf4, and cMyc genes is associated with the development ofmultiple tumors known in oncogenetics [22, 24]. In particular, the overexpression of Oct4 causes murine epithelial cell dysplasia [25],the aberrant expression of Sox2 causes the development of serrated polypsand mucinous colon carcinomas [26], breast tumors arecharacterized by elevated expression of Klf4 [27] , and the improper expression of cMyc is observed in 70% of human cancers [28].Tumor development is oberved in ~50% of murine chimeras obtained through the injection ofretroviral iPSCs into blastocysts, which is very likely associated with thereactivation of exogenous cMyc [29, 30].

Several possible strategies exist for resolving the above-mentioned problems:

The search for a less carcinogenic gene set that is necessary and sufficient for reprogramming;

The minimization of the number of genes required for reprogramming and searching for the nongenetic factors facilitating it;

The search for systems allowing the elimination of the exogenous DNA from the host cell genome after the reprogramming;

The development of delivery protocols for nonintegrated genetic constructs;

The search for ways to reprogram somatic cells using recombinant proteins.

The ectopic expression of cMyc and Klf4 genes isthe most dangerous because of the high probability that malignant tumors will develop [22]. Hence the necessity to find other genes that couldsubstitute cMyc and Klf4 in iPSC production. Ithas been reported that these genes can be successfully substituted by Nanog and Lin28 for reprogramming human somatic cells [18;] . iPSCs were prepared from murine embryonic fibroblastsby the overexpression of Oct4 and Sox2 , as well as the Esrrb gene encoding the murine orphan nuclear receptor beta. It has alreadybeen shown that Esrrb , which acts as a transcription activator of Oct4 , Sox2 , and Nanog , is necessary for theselfrenewal and maintenance of the pluripotency of murine ESCs. Moreover, Esrrb can exert a positive control over Klf4 . Thus, the genes causingelevated carcinogenicity of both iPSCs and their derivatives can besuccessfully replaced with less dangerous ones [31].

The Most Effectively Reprogrammed Cell Lines . Murine and humaniPSCs can be obtained from fibroblasts using the factors Oct4, Sox2, and Klf4,but without cMyc . However, in this case, reprogramming deceleratesand an essential shortcoming of stable iPSC clones is observed [32, 33]. The reduction of a number ofnecessary factors without any decrease in efficiency is possible when iPSCsare produced from murine and human neural stem cells (NSCs) [12, 34, 35]. For instance, iPSCs were produced fromNSCs isolated from adult murine brain using two factors, Oct4 and Klf4, aswell as even Oct4 by itself [12, 34]. Later, human iPSCs were produced by the reprogramming offetal NSCs transduced with a retroviral vector only carrying Oct4 [35] . It is most likely that the irrelevanceof Sox2, Klf4, and cMyc is due to the high endogenous expression level of these genes inNSCs.

Successful reprogramming was also achieved in experiments withother cell lines, in particular, melanocytes of neuroectodermal genesis [36]. Both murine and human melanocytes are characterized by a considerableexpression level of the Sox2 gene, especially at early passages.iPSCs from murine and human melanocytes were produced without the use of Sox2or cMyc. However, the yield of iPSC clones produced from murine melanocytes was lower(0.03% without Sox2 and 0.02% without cMyc) in comparison with that achieved when allfour factors were applied to melanocytes (0.19%) and fibroblasts (0.056%). A decreasedefficiency without Sox2 or cMyc was observed in human melanocyte reprogramming (0.05%with all four factors and 0.01% without either Sox2 or cMyc ). All attempts to obtain stable iPSC clones in the absence of both Sox2 andcMyc were unsuccessful [36]. Thus, theminimization of the number of factors required for iPSC preparation can be achieved by choosingthe proper somatic cell type that most effectively undergoes reprogramming under the action offewer factors, for example, due to the endogenous expression of pluripotencygenes. However, if human iPSCs are necessary, these somatic cellsshould be easily accessible and wellcultured and their method of isolation should be asnoninvasive as possible.

One of these cell types can be adipose stem cells (ASCs). This is aheterogeneous group of multipotent cells which can be relatively easily isolated in largeamounts from adipose tissue following liposuction. Human iPSCs weresuccessfully produced from ASCs with a twofold reprogramming rate and20fold efficiency (0.2%), exceeding those of fibroblasts [37].

However, more accessible resources for the effective production of humaniPSCs are keratinocytes. When compared with fibroblasts, human iPSC productionfrom keratinocytes demonstrated a 100fold greater efficiency and a twofold higherreprogramming rate [38].

It has recently been found that the reprogramming of murine papillary dermal fibroblasts(PDFs) into iPSCs can be highly effective with theoverexpression of only two genes, Oct4 and Klf4 ,inserted into retroviral vectors [39;].PDFs are specialized cells of mesodermal genesis surrounding the stem cells ofhair follicles . One characteristic feature of these cells is the endogenous expression of Sox2 , Klf4 , and cMyc genes,as well as the geneencoding alkaline phosphatase, one of the murine and humanESC markers. PDFs can be easily separated from other celltypes by FACS (fluorescenceactivated cell sorting) using life staining with antibodiesagainst the surface antigens characteristic of one or another cell type. The PDF reprogrammingefficiency with the use of four factors (Oct4, Sox2, Klf4, and cMyc) retroviral vectorsis 1.38%, which is 1,000fold higher than the skin fibroblast reprogramming efficiency inthe same system. Reprogramming PDFs with two factors, Oct4 and Klf4 , yields 0.024%, which is comparable to the efficiency of skinfibroblast reprogramming using all four factors. The efficiency of PDF reprogramming iscomparable with that of NSCs, but PDF isolation is steady and far lessinvasive [39]. It seems likely that human PDF lines arealso usable, and this cell type may appear to be one of the most promising for human iPSCproduction in terms of pharmacological studies and cell replacement therapy. The use of suchcell types undergoing more effective reprogramming, together with methods providing thedelivery of pluripotency genes without the integration of foreign DNA into thehost genome and chemical compounds increasing the reprogramming efficiency and substitutingsome factors required for reprogramming, is particularly relevant.

Chemical Compounds Increasing Cell Reprogramming Efficiency. As was noted above,the minimization of the factors used for reprogramming decreases the efficiency of iPSCproduction. Nonetheless, several recent studies have shown that the use of genetic mechanisms,namely, the initiation of ectopic gene expression, can be substituted by chemical compounds,most of them operating at the epigenetic level. For instance, BIX01294 inhibitinghistone methyltransferase G9a allows murine fibroblast reprogramming using only two factors,Oct4 and Klf4, with a fivefold increased yield of iPSC clones in comparison with the controlexperiment without BIX01294 [40]. BIX01294taken in combination with another compound can increase the reprogramming efficiency even more.In particular, BIX01294 plus BayK8644 elevated the yield of iPCSs 15 times, andBIX01294 plus RG108 elevated it 30 times when only two reprogramming factors, Oct4 andKlf4, were used. RG108 is an inhibitor of DNA methyltransferases, and its role in reprogrammingis apparently in initiating the more rapid and effective demethylation of promoters ofpluripotent cellspecific genes, whereas BayK8644 is an antagonist of Ltypecalcium channels, and its role in reprogramming is not understood very well [40]. However, more considerable results were obtained inreprogramming murine NSCs. The use of BIX01294 allowed a 1.5foldincrease in iPSC production efficiency with two factors, Oct4 and Klf4, in comparison withreprogramming with all four factors. Moreover, BIX01294 can even substitute Oct4 in thereprogramming of NSCs, although the yield is very low [41]. Valproic (2propylvaleric) acid inhibiting histone deacetylases canalso substitute cMyc in reprogramming murine and human fibroblasts. Valproic acid (VPA)increases the reprogramming efficiency of murine fibroblasts 50 times, and human fibroblastsincreases it 1020 times when three factors are used [42, 43]. Other deacetylase inhibitors,such as TSA (trichostatin A) and SAHA (suberoylanilide hyroxamic acid), also increase thereprogramming efficiency. TSA increases the murine fibroblast reprogramming efficiency 15times, and SAHA doubles it when all four factors are used [42]. Besides epigenetic regulators, the substances inhibiting the proteincomponents of signaling pathways implicated in the differentiation of pluripotent cells arealso applicable in the substitution of reprogramming factors. In particular, inhibitors of MEKand GSK3 kinases (PD0325901 and CHIR99021, respectively) benefit the establishment of thecomplete and stable pluripotency of iPSCs produced from murineNSCs using two factors, Oct4 and Klf4 [41, 44].

It has recently been shown that antioxidants can considerably increase the efficiency ofsomatic cell reprogramming. Ascorbic acid (vitamin C) can essentially influence the efficiencyof iPSC production from various murine and human somatic cell types [45]. The transduction of murine embryonic fibroblasts (mEFs) with retrovirusescarrying the Oct4 , Sox2 , and Klf4 genes results in a significant increase in the production level of reactive oxygen species(ROS) compared with that of both control and Efs tranduced with Oct4 , Sox2 , cMyc , and Klf4 . Inturn, the increase in the ROS level causes accelerated aging and apoptosis of the cell, whichshould influence the efficiency of cell reprogramming. By testing several substances possessingantioxidant activity such as vitamin B1, sodium selenite, reduced glutathione, and ascorbicacid, the authors have found that combining these substances increases the yield ofGFPpositive cells in EF reprogramming (the Gfp genewas under the control of the Oct4 gene promoter). The use of individualsubstances has shown that only ascorbate possesses a pronounced capability to increase thelevel of GFPpositive cells, although other substances keep theirROSdecreasing ability. In all likelihood, this feature of ascorbates is not directlyassociated with its antioxidant activity [45]. The scoreof GFPpositive iPSC colonies expressing an alkaline phosphatase hasshown that the efficiency of iPSC production from mEFs with three factors (Oct4, Sox2, andKlf4) can reach 3.8% in the presence of ascorbate. When all four factors (Oct4, Sox2, Klf4, andcMyc) are used together with ascorbate, the efficiency of iPSC production may reach8.75%. A similar increase in the iPSC yield was also observed in the reprogramming of murinebreast fibroblasts; i.e., the effect of vitamin C is not limited by one cell type. Moreover,the effect of vitamin C on the reprogramming efficiency is more profound than that of thedeacetylase inhibitor valproic (2propylvaleric) acid. The mutual effect of ascorbate andvalproate is additive; i.e., these substances have different action mechanisms. Moreover,vitamin C facilitates the transition from preiPSCs to stablepluripotent cells. This feature is akin to the effects of PD0325901 and CHIR99021, which areinhibitors of MEK and GSK3 kinases, respectively. This effect of vitamin C expands to humancells as well [45]. Following the transduction of humanfibroblasts with retroviruses carrying Oct4 , Sox2 , Klf4 , and cMyc and treatment with ascorbate, theauthors prepared iPSCs with efficiencies reaching 6.2%. The reprogrammingefficiency of ASCs under the same conditions reached 7.06%. The mechanism ofthe effect that vitamin C has on the reprogramming efficiency is not known in detail.Nevertheless, the acceleration of cell proliferation was observed at the transitional stage ofreprogramming. The levels of the p53 and p21 proteins decreased in cells treated withascorbate, whereas the DNA repair machinery worked properly [45]. It is interesting that an essential decrease in the efficiency of iPSCproduction has been shown under the action of processes initiated by p53 and p21 [4650].

As was mentioned above, for murine and human iPSC production, both retro andlentiviruses were initially used as delivery vectors for the genes required for cellreprogramming. The main drawback of this method is the uncontrolled integration of viral DNAinto the host cells genome. Several research groups have introduced methods fordelivering pluripotency genes into the recipient cell which either do notintegrate allogenic DNA into the host genome or eliminate exogenous genetic constructs from thegenome.

CreloxP Mediated Recombination. To prepareiPSCs from patients with Parkinsons disease, lentiviruses were used,the proviruses of which can be removed from the genome by Cre recombinase. To do this, the loxP site was introduced into thelentiviral 3LTRregions containing separate reprogramming genesunder the control of the doxycyclineinducible promoter. During viral replication, loxP was duplicated in the 5LTR of the vector. As aresult, the provirus integrated into the genome was flanked with two loxP sites. The inserts were eliminated using the temporary transfection ofiPSCs with a vector expressing Cre recombinase[51].

In another study, murine iPSCs were produced using a plasmid carrying the Oct4 , Sox2 , Klf4I, and cMyc genes in the same reading frame in which individual cDNAs were separatedby sequences encoding 2 peptides, and practically the whole construct was flanked with loxP sites [52]. The use ofthis vector allowed a notable decrease in the number of exogenous DNA inserts in the hostcells genome and, hence, the simplification of their following excision [52]. It has been shown using lentiviruses carrying similarpolycistronic constructs that one copy of transgene providing a high expression level of theexogenous factors Oct4, Sox2, Klf4, and cMyc is sufficient for the reprogramming ofdifferentiated cells into the pluripotent state [53,54].

The drawback of the CreloxP system is the incomplete excisionof integrated sequences; at least the loxP site remains in thegenome, so the risk of insertion mutations remains.

Plasmid Vectors . The application of lentiviruses and plasmids carrying the loxP sites required for the elimination of transgene constructsmodifies, although insignificantly, the host cells genome. One way to avoid this is touse vector systems that generally do not provide for the integration of the whole vector orparts of it into the cells genome. One such system providing a temporary transfectionwith polycistronic plasmid vectors was used for iPSC production from mEFs [29]. A polycistronic plasmid carrying the Oct4 , Sox2 , and Klf4 gene cDNAs, as well as aplasmid expressing cMyc , was transfected into mEFs one, three, five,and seven days after their primary seeding. Fibroblasts were passaged on the ninth day, and theiPSC colonies were selected on the 25th day. Seven out of ten experiments succeeded inproducing GFPpositive colonies (the Gfp gene wasunder the control of the Nanog gene promoter). The iPSCsthat were obtained were similar in their features to murine ESCs and did not contain inserts ofthe used DNA constructs in their genomes. Therefore, it was shown that wholesome murineiPSCs that do not carry transgenes can be reproducibly produced, and that thetemporary overexpression of Oct4 , Sox2 , Klf4 , and cMyc is sufficient for reprogramming. The maindrawback of this method is its low yield. In ten experiments the yield varied from 1 to 29 iPSCcolonies per ten million fibroblasts, whereas up to 1,000 colonies per ten millions wereobtained in the same study using retroviral constructs [29].

Episomal Vectors . Human iPSCs were successfully produced fromskin fibroblasts using single transfection with polycistronic episomal constructs carryingvarious combinations of Oct4 , Sox2 , Nanog , Klf4 , cMyc , Lin28 , and SV40LT genes. These constructs were designed on the basis of theoriP/EBNA1 (EpsteinBarr nuclear antigen1) vector [55]. The oriP/EBNA1 vector contains the IRES2 linker sequence allowing theexpression of several individual cDNAs (encoding the genes required for successfulreprogramming in this case) into one polycistronic mRNA from which several proteins aretranslated. The oriP/EBNA1 vector is also characterized by lowcopy representation in thecells of primates and can be replicated once per cell cycle (hence, it is not rapidlyeliminated, the way common plasmids are). Under nonselective conditions, the plasmid iseliminated at a rate of about 5% per cell cycle [56]. Inthis work, the broad spectrum of the reprogramming factor combinations was tested, resulting inthe best reprogramming efficiency with cotransfection with three episomes containing thefollowing gene sets: Oct4 + Sox2 + Nanog + Klf4 , Oct4 + Sox2 + SV40LT + Klf4 , and cMyc + Lin28 . SV40LT ( SV40 large T gene )neutralizes the possible toxic effect of overexpression [57]. The authors have shown thatwholesome iPSCs possessing all features of pluripotent cells can be producedfollowing the temporary expression of a certain gene combination in human somatic cells withoutthe integration of episomal DNA into the genome. However, as in the case when plasmid vectorsare being used, this way of reprogramming is characterized by low efficiency. In separateexperiments the authors obtained from 3 to 6 stable iPSC colonies per 106transfected fibroblasts [55]. Despite the fact that skinfibroblasts are wellcultured and accessible, the search for other cell types which arerelatively better cultured and more effectively subject themselves to reprogramming throughthis method is very likely required. Another drawback of the given system is that this type ofepisome is unequally maintained in different cell types.

PiggyBacTransposition . One promising system used foriPSC production without any modification of the host genome is based on DNA transposons.Socalled PiggyBac transposons containing2linkered reprogramming genes localized between the 5 and3terminal repeats were used for iPSC production from fibroblasts. The integrationof the given constructs into the genome occurs due to mutual transfection with a plasmidencoding transposase. Following reprogramming due to the temporary expression of transposase,the elimination of inserts from the genome took place [58, 59]. One advantage of the PiggyBac system on CreloxP is that the exogenous DNA iscompletely removed [60].

However, despite the relatively high efficiency of exogenous DNA excision from the genome by PiggyBac transposition, the removal of a large number of transposoncopies is hardly achievable.

Nonintegrating Viral Vectors . Murine iPSCs were successfullyproduced from hepatocytes and fibroblasts using four adenoviral vectors nonintegrating into thegenome and carrying the Oct4 , Sox2 , Klf4 , and cMyc genes. An analysis of the obtainediPSCs has shown that they are similar to murine ESCs in their properties(teratoma formation, gene promoter DNA methylation, and the expression of pluripotent markers),but they do not carry insertions of viral DNA in their genomes [61]. Later, human fibroblastderived iPSCs wereproduced using this method [62].

The authors of this paper cited the postulate that the use of adenoviral vectors allows theproduction of iPSCs, which are suitable for use without the risk of viral oroncogenic activity. Its very low yield (0.00010.001%), the deceleration ofreprogramming, and the probability of tetraploid cell formation are the drawbacks of themethod. Not all cell types are equally sensitive to transduction with adenoviruses.

Another method of gene delivery based on viral vectors was recently employed for theproduction of human iPSCs. The sendaivirus (SeV)based vector wasused in this case [63]. SeV is a singlestrandedRNA virus which does not modify the genome of recipient cells; it seems to be a good vector forthe expression of reprogramming factors. Vectors containing either all pluripotencyfactors or three of them (without ) were used for reprogramming the human fibroblast. The construct based on SeV is eliminatedlater in the course of cell proliferation. It is possible to remove cells with the integratedprovirus via negative selection against the surface HN antigen exposed on the infected cells.The authors postulate that reprogramming technology based on SeV will enable the production ofclinically applicable human iPSCs [63].

Cell Transduction with Recombinant Proteins . Although the methods for iPSCproduction without gene modification of the cells genome (adenoviral vectors, plasmidgene transfer, etc.) are elaborated, the theoretical possibility for exogenous DNA integrationinto the host cells genome still exists. The mutagenic potential of the substances usedpresently for enhancing iPSC production efficiency has not been studied in detail. Fullychecking iPSC genomes for exogenous DNA inserts and other mutations is a difficult task, whichbecomes impossible to solve in bulk culturing of multiple lines. The use of protein factorsdelivered into a differentiated cell instead of exogenous DNA may solve this problem. Tworeports have been published to date in which murine and human iPSCs wereproduced using the recombinant Oct4, Sox2, Klf4, and cMyc proteins [64, 65] . T he methodused to deliver the protein into the cell is based on the ability of peptides enriched withbasic residues (such as arginine and lysine) to penetrate the cells membrane. MurineiPSCs were produced using the recombinant Oct4, Sox2, Klf4, and cMycproteins containing eleven Cterminal arginine residues and expressed in E. coli . The authors succeeded in producing murine iPSCs during four roundsof protein transduction into embryonic fibroblasts [65].However, iPSCs were only produced when the cells were additionally treatedwith 2propylvalerate (the deacetylase inhibitor). The same principle was used for theproduction of human iPSCs, but protein expression was carried out in humanHEK293 cells, and the proteins were expressed with a fragment of nine arginins at the proteinCend. Researchers have succeeded in producing human iPSCs after sixtransduction rounds without any additional treatment [64]. The efficiency of producing human iPSC in this way was 0.001%, which isone order lower than the reprogramming efficiency with retroviruses. Despite some drawbacks,this method is very promising for the production of patientspecificiPSCs.

The first lines of human pluripotent ESCs were produced in 1998 [6]. In line with the obvious fundamental importance of embryonic stem cellstudies with regard to the multiple processes taking place in early embryogenesis, much of theinterest of investigators is associated with the possibility of using ESCs and theirderivatives as models for the pathogenesis of human diseases, new drugs testing, and cellreplacement therapy. Substantial progress is being achieved in studies on directed humanESC differentiation and the possibility of using them to correct degenerativedisorders. Functional cell types, such as motor dopaminergic neurons, cardiomyocytes, andhematopoietic cell progenitors, can be produced as a result of ESCdifferentiation. These cell derivatives, judging from their biochemical and physiologicalproperties, are potentially applicable for the therapy of cardiovascular disorders, nervoussystem diseases, and human hematological disorders [66].Moreover, derivatives produced from ESCs have been successfully used for treating diseasesmodeled on animals. Therefore, bloodcell progenitors produced from ESCs weresuccessfully used for correcting immune deficiency in mice. Visual functions were restored inblind mice using photoreceptors produced from human ESCs, and the normal functioning of thenervous system was restored in rats modeling Parkinsons disease using the dopaminergicneurons produced from human ESCs [6770]. Despite obvious success, the fullscale applicationof ESCs in therapy and the modeling of disorders still carry difficulties, because of thenecessity to create ESC banks corresponding to all HLAhaplotypes, whichis practically unrealistic and hindered by technical and ethical problems.

Induced pluripotent stem cells can become an alternative for ESCs in the area of clinicalapplication of cell replacement therapy and screening for new pharmaceuticals.iPSCs closely resemble ESCs and, at the same time, can be produced in almostunlimited amounts from the differentiated cells of each patient. Despite the fact that thefirst iPSCs were produced relatively recently, work on directed iPSCdifferentiation and the production of patientspecific iPSCs isintensive, and progress in this field is obvious.

Dopamine and motor neurons were produced from human iPSCs by directeddifferentiation in vitro [71, 72]. These types of neurons are damaged in many inherited oracquired human diseases, such as spinal cord injury, Parkinsons disease, spinal muscularatrophy, and amyotrophic lateral sclerosis. Some investigators have succeeded in producingvarious retinal cells from murine and human iPSCs [7375]. HumaniPSCs have been shown to be spontaneously differentiated in vitro into the cells of retinal pigment epithelium [76]. Another group of investigators has demonstrated that treating human andmurine iPSCs with Wnt and Nodal antagonists in a suspended culture induces theappearance of markers of cell progenitors and pigment epithelium cells. Further treating thecells with retinoic acid and taurine activates the appearance of cells expressing photoreceptormarkers [75].

Several research groups have produced functional cardiomyocytes (CMs) in vitro from murine and human iPSCs [7781]. Cardiomyocytes producedfrom iPSC are very similar in characteristics (morphology, marker expression,electrophysiological features, and sensitivity to chemicals) to the CMs ofcardiac muscle and to CMs produced from differentiated ESCs. Moreover, murineiPSCs, when injected, can repair muscle and endothelial cardiac tissuesdamaged by cardiac infarction [77].

Hepatocytelike cell derivatives, dendritic cells, macrophages, insulinproducingcell clusters similar to the duodenal islets of Langerhans, and hematopoietic and endothelialcells are currently produced from murine and human iPSCs, in addition to thealreadylisted types of differentiated cells [8285].

In addition to directed differentiation in vitro , investigators apply mucheffort at producing patientspecific iPSCs. The availability ofpluripotent cells from individual patients makes it possible to study pathogenesis and carryout experiments on the therapy of inherited diseases, the development of which is associatedwith distinct cell types that are hard to obtain by biopsy: so the use ofiPSCs provides almost an unlimited resource for these investigations.Recently, the possibility of treating diseases using iPSCs was successfullydemonstrated, and the design of the experiment is presented in the figure. A mutant allele wassubstituted with a normal allele via homologous recombination in murine fibroblastsrepresenting a model of human sickle cell anemia. iPSCs were produced fromrepaired fibroblasts and then differentiated into hematopoietic cell precursors.The hematopoietic precursors were then injected into a mouse from which the skin fibroblastswere initially isolated (). As a result, the initialpathological phenotype was substantially corrected [86].A similar approach was applied to the fibroblasts and keratinocytes of a patient withFanconis anemia. The normal allele of the mutant gene producing anemia was introducedinto a somatic cell genome using a lentivirus, and then iPSCs were obtainedfrom these cells. iPSCs carrying the normal allele were differentiated intohematopoietic cells maintaining a normal phenotype [87].The use of lentiviruses is unambiguously impossible when producing cells to be introduced intothe human body due to their oncogenic potential. However, new relatively safe methods of genomemanipulation are currently being developed; for instance, the use of synthetic nucleasescontaining zinc finger domains allowing the effective correction of genetic defects invitro [88].

Design of an experiment on repairing the mutant phenotype in mice modeling sickle cell anemia development [2]. Fibroblasts isolatedfrom the tail of a mouse (1) carrying a mutant allele of the gene encoding the human hemoglobin -chain (hs) were used for iPSCproduction (2). The mutation was then repaired in iPSCs by means of homological recombination (3) followed by cell differentiationvia the embryoid body formation (4). The directed differentiation of the embryoid body cells led to hematopoietic precursor cells (5)that were subsequently introduced into a mouse exposed to ionizing radiation (6).

The induced pluripotent stem cells are an excellent model for pathogenetic studies at the celllevel and testing compounds possessing a possible therapeutic effect.

The induced pluripotent stem cells were produced from the fibroblasts of a patient with spinalmuscular atrophy (SMA) (SMAiPSCs). SMA is an autosomalrecessive disease caused by a mutation in the SMN1 ( survival motorneuron 1 ) gene, which is manifested as the selective nonviability of lower motor neurons. Patients with this disorder usually die at the age of about two years.Existing experimental models of this disorder based on the use of flatworms, drosophila, andmice are not satisfactory. The available fibroblast lines from patients withSMA cannot provide the necessary data on the pathogenesis of this disordereither. It was shown that motor neurons produced from SMAiPSCs canretain the features of SMA development, selective neuronal death, and the lackof SMN1 transcription. Moreover, the authors succeeded in elevating the SMNprotein level and aggregation (encoded by the SMN2 gene, whose expressioncan compensate for the shortage in the SMN1 protein) in response to the treatment of motorneurons and astrocytes produced from SMAiPSCs with valproate andtorbomycin [89;]. iPSCs and theirderivatives can serve as objects for pharmacological studies, as has been demonstrated oniPSCs from patients with familial dysautonomia (FDA) [90]. FDA is an inherited autosomal recessive disorder manifested as thedegeneration of sensor and autonomous neurons. This is due to a mutation causing thetissuespecific splicing of the IKBKAP gene, resulting in a decreasein the level of the fulllength IKAP protein. iPSCs were produced fromfibroblasts of patients with FDA. They possessed all features of pluripotent cells. Neuralderivatives produced from these cells had signs of FDA pathogenesis and low levels of thefulllength IKBKAP transcript. The authors studied the effect of threesubstances, kinetin, epigallocatechin gallate, and tocotrienol, on the parameters associatedwith FDA pathogenesis. Only kinetin has been shown to induce an increase in the level offulllength IKBKAP transcript. Prolonged treatment with kinetininduces an increase in the level of neuronal differentiation and expression of peripheralneuronal markers.

Currently, a broad spectrum of iPSCs is produced from patients with variousinherited pathologies and multifactorial disorders, such as Parkinsons disease, Downsyndrome, type 1 diabetes, Duchenne muscular dystrophy, talassemia, etc., whichare often lethal and can scarcely be treated with routine therapy [51, 87, 89, 9194]. The data on iPSCs produced by reprogramming somaticcells from patients with various pathologies are given in the .

Functional categories of M. tuberculosis genes with changed expression level during transition to the NC state

One can confidently state that both iPSCs themselves and their derivativesare potent instruments applicable in biomedicine, cell replacement therapy, pharmacology, andtoxicology. However, the safe application of iPSCbased technologies requires the use ofmethods of iPSCs production and their directed differentiation which minimizeboth the possibility of mutations in cell genomes under in vitro culturingand the probability of malignant transformation of the injected cells. The development ofmethods for human iPSC culturing without the use of animal cells (for instance, the feederlayer of murine fibroblasts) is necessary; they make a viralorigin pathogen transferfrom animals to humans impossible. There is a need for the maximum standardization ofconditions for cell culturing and differentiation.

This study was supported by the Russian Academy of Sciences Presidium ProgramMolecular and Cell Biology.

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Induced Pluripotent Stem Cells: Problems and Advantages ...

Skin Stem Cells Comments Off on Induced Pluripotent Stem Cells: Problems and Advantages … | April 15th, 2022

Somatic stem cells (also called adult stem cells) exist naturally in the body. They are important for growth, healing, and replacing cells that are lost through daily wear and tear.

Stem cells from the blood and bone marrow are routinely used as a treatment for blood-related diseases. However, under natural circumstances somatic stem cells can become only a subset of related cell types. Bone marrow stem cells, for example, differentiate primarily into blood cells. This partial differentiation can be an advantage when you want to produce blood cells; but it is a disadvantage if you're interested in producing an unrelated cell type.

Most types of somatic stem cells are present in low abundance and are difficult to isolate and grow in culture. Isolation of some types could cause considerable tissue or organ damage, as in the heart or brain. Somatic stem cells can be transplanted from donor to patient, but without drugs that suppress the immune system, a patient's immune system will recognize transplanted cells as foreign and attack them.

Therapy involving somatic stem cells is not controversial; however, it is subject to the same ethical considerations that apply to all medical procedures.

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Stem Cell Quick Reference - University of Utah

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It can be difficult to figure out what products are worth your money in such a saturated beauty space, but here are two telltale signs: If celebrities recommend the product without being paid and if beauty editors, who get sent free products to test on the regular, say theyd spend their own money on it, chances are the product is worth a place in your routine.

Augustinus Baders The Cream (for combination and oily skin) and The Rich Cream (for dry skin) check both these boxes. The Creams word-of-mouth testimonials have given the product cult-level status. In fact, its been recommended three separate times in I Swear By This, a franchise where creatives share their must-have beauty products.

I felt like this product came out of nowhere; like one day, it popped up and everyone was recommending it. I have really sensitive skin, so Im typically hesitant to try new products, but I gave this a go. When I woke up the next day, I was a believer. Everything that everyone says about this cream is true. The price point is definitely on the higher end, but its so worth it. Grace Pae, celebrity makeup artist

"This has become central to not just my routine, but the routine of many of our customers. We were the first platform to launch this product, and it was really excitingthe whole experience of discovering this beauty holy grail. It's been a best-seller since it launched." Cassandra Grey, founder of beauty e-commerce platform Violet Grey

If its good enough for burn victims, its good enough for me. It's expensive, but some stuff you can't really put a price on. Plus, Im not using that much. My girlfriend buys it, so its all over the house. Basically, when she's not around, I use it, so I dont get slapped on the wrist.

This is an interesting product because its become the hot chick thing. They sell this at The Row; its the one. Every two to three years, theres a product like that. I don't even know if it's celebrity-driven because, with anything that becomes as big and popular as this, its just because it's good and it works.

Skin care and beauty are so personal. You can't just have beautiful packaging and marketing. It really does have to work, and there has to be a word-of-mouth element. That criteria doesn't exist in other categories. Chris Black, writer, consultant, and co-host of the podcast How Long Gone

Given all the hype the product has received, I decided to try it out myself. Below, my review on Augustinus Bader The Cream.

The Formula

In 2008, Augustinus Bader, a professor of applied stem cell biology and cell technology at the University of Leipzig in Germany, formulated a wound gel that heals third-degree burns, without surgery. The eponymous skin-care line was born from this breakthrough. The ethos behind Baders work is the idea that your skin doesnt need a never-ending supply of new ingredients.

Our skin contains stem cells, which have healing and regenerative properties. However, according to research, in order to trigger the self-renewal process, the environment needs to give the stem cells a green light to do their job. If theyre not receiving signals to activate, the skin stem cells lay dormant.

Both creams are formulated with Trigger Factor Complex, which contains vitamins, peptides, amino acids, and lipidsingredients that nourish the environment and signal to the dormant stem cells to wake up. Once the bodys stem cells are activated, the healing process promotes skin-care benefits like reducing redness, fading hyperpigmentation, and minimizing the appearance of fine lines and wrinkles.

The Results

After years of hearing the buzz about the brand, I decided to give it a try to see if the cream was actually as good as people say. I have combination skin thats prone to dehydration and dark spots, so I chose The Cream over The Rich Cream. The brand recommends using the product for at least 27 days (the amount of time it takes for cell turnover to occur). They also suggest using it alone, with no other skin-care products aside from cleanser. However, I decided to work The Cream into my existing morning and evening routines. After cleansing, Id apply the product before layering my other serums on top.

Before

After

The Cream played well with the other products in my routine. Its lightweight texture glided smoothly across my skin and the formula didnt dry down stickythere was no greasy residue left behind. My skin felt (and looked) plump after applying and it absorbed quickly. After a couple weeks of using The Cream, I started to notice a difference. My skin, which usually looks dull and extra parched in the mornings, felt supple and looked dewy. My stubborn dark spots were beginning to fade. Overall, my complexion looked healthier.

I still have a couple of weeks to go before I hit the 27-day mark, but The Cream has quickly become a staple in my routine. Yes, its pricey, but because of its clinically backed formula and proven performance, I think its absolutely worth the money.

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Augustinus Bader The Cream Review - Coveteur

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Get the Highest Quality Multi Collagen Powder Highest Quality Multi Collagen Powder

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Collagen has become a popular hair growth supplement thanks to media attention and personal reports from consumers, despite a lack of scientific evidence linking collagen to hair growth.

Collagen is the most abundant protein in the human body, and it helps build and repair bones, tendons, ligaments, muscles, hair and skin, including skin on the scalp.

Some studies have shown that taking collagen improves hair growth, but most of these studies were funded by the cosmetic and supplement industries.According to the Harvard T.H. Chan School of Public Health, this presents a conflict of interest because most of the research on collagen supplements is funded by related industries that may benefit from positive results.

People have claimed that collagen supplementation can help regenerate hair follicles to regrow hair, thicken hair density, stop hair loss and possibly impact hair graying.

More objective and controlled studies are necessary to determine whether collagen supplementation may live up to these claims.

Collagen plays important roles in the health of the scalp and hair follicles, and it contains amino acids used to build keratin, which is the protein that hair is primarily made of.

Collagen is the primary component of the dermis, which is the connective tissue layer that contains hair follicles. Collagen plays a role repairing the dermis and the skin on the scalp at the base of the hair follicle, and it may impact age-related hair growth.

The following studies reported no conflicts of interest or suspicious funding sources.

An August 2021 study published in Aging investigated the role collagen may play in hair follicle regeneration. Tests showed that younger cells at the base of hair follicles upregulated (used more) collagen, while aged cells downregulated (used less) collagen. The young cells also aggregated together, which promotes hair follicle growth, while the aged cells had difficulty aggregating.

These results suggest that collagen helps younger people regenerate hair follicles, which lead to hair growth. As people age and collagen levels drop, there is less hair follicle regeneration and subsequent hair loss.

According to a 2018 study published in Experimental Dermatology, collagen type 17 is an important part of the microenvironment that promotes hair follicle stem cell health. Hair follicle stem cells become active during a new hair cycle, which is when new hair growth occurs.

The study also reported that people born with an inability to make collagen type 17 develop junctional epidermolysis bullosa, which is a genetic condition that causes skin to be fragile and blister. Patients with this condition develop serious hair loss and hair graying early in life.

Mice genetically altered to be deficient in type 17 collagen also develop hair loss and graying. Researchers reported that graying is believed to occur after collagen breakdown around hair follicle stem cells.

A 2016 study published in Science evaluated the effects of supplementing type 17 collagen in aged mice with hair loss. Results showed that maintaining levels of type 17 collagen helped aged hair follicles use collagen again to restore cell function and health.

Type 17 collagen is not available in supplement form but supplementing with different types of collagen may provide a wide range of amino acids the body needs to produce type 17 collagen.

Type I collagen is considered one of the best types for skin and hair, and it is found in both marine and bovine sources of collagen. This type of collagen is rich in hydroxyproline, which helps build keratin and is essential for skin health.

CB Supplements offers the highest quality multi collagen powder thats naturally formulated to keep your joints, skin, hair, nails and gut healthy.

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Taking collagen may improve the health of your scalp and hair, but there isnt much objective evidence that it will result in hair growth for everyone who takes it. Other potential collagen benefits include improvements in the health of skin, joints and bones.

Supplementing with collagen powder may promote the health and function of the scalp and hair follicles, but it must be taken on a long-term basis because the body produces an enzyme that constantly breaks down collagen.

Dietary supplements, including collagen supplements, are not reviewed by the U.S. Food and Drug Administration before they reach the U.S. market. It is important to look for a third-party verification seal on supplements before you buy them.

Examples of third-party verification organizations in the U.S. include the U.S. Pharmacopeia and NSF International. U.S. Pharmacopeia ensures that the ingredients have been verified, and NSF International certifies that a products ingredients match the label.

Make sure to discuss any new supplement with a doctor to review possible side effects, drug interactions and allergies. Collagen may be sourced from fish and eggs, which are common allergens.

Ask your doctor if any digestive problems could result from recommended dose and whether you should try a particular form of supplement first.

While there are no known drug interactions with collagen, some collagen supplements contain other ingredients, such as vitamin C, that may interact with drugs. Vitamin C should not be taken with bortezomib or deferoxamine.

Please seek the advice of a medical professional before making health care decisions.

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Collagen for Hair Growth | The Benefits It Has on Your Hair - DrugWatch.com

Skin Stem Cells Comments Off on Collagen for Hair Growth | The Benefits It Has on Your Hair – DrugWatch.com | April 15th, 2022

Skin cells have been exposed to molecules that reverse their development but still retain their function, creating a kind of stem cell that keeps its original function in the body

By Chen Ly

A fluorescent light micrograph of fibroblast cells from human skin

VSHYUKOVA/SCIENCE PHOTO LIBRARY

Researchers have developed a method that can turn back the biological clock on skin cells by 30 years, creating stem cells from mature ones, which could be used to treat skin conditions in the future.

In 2007, Shinya Yamanaka at Kyoto University in Japan developed a technique that could transform adult skins cells into stem cells by inserting four specialist molecules, dubbed Yamanaka factors, that reverse cell development. It takes around 50 days of exposure to these molecules for normal cells to be reprogrammed into what are known as induced pluripotent stem cells (iPSCs).

When you turn to a cell into an iPSC, you lose the original cell type and its functionality, says Diljeet Gill at the Babraham Institute in Cambridge, UK.

Gill and his colleagues have now devised a technique that uses Yamanaka factors to rejuvenate skin cells without losing their previous functionality.

The researchers collected skin cell samples from three human donors that had an average age of around 50, then exposed these to the Yamanaka factors for just 13 days to partially anti-age the cells. They then removed the Yamanaka factors and left the cells to grow.

As we age, our DNA gets tagged with chemicals, so tracking these markers can help us determine how old our bodies are. This is known as our epigenetic clock. Over time, some of our genes will either turn on or off, the collection of which is known as the transcriptome.

Gill and his team found that the epigenetic clock and transcriptome profiles of the partially reprogrammed cells matched the profiles of skin cells that belonged to people who were 30 years younger.

The rejuvenated cells also functioned like younger ones, too, creating more collagen than those that didnt undergo reprogramming. And when placed onto an artificial wound, the reprogrammed cells moved to close the gap much quicker than the older ones did.

In young people, if you cut yourself, itll take quicker to heal the wound, while it would take me longer to heal, says team member Wolf Reik, also at the Babraham Institute. Its very exciting not only the molecular read-outs that are younger, but the cell also functions more like young cells.

The key advance in this study is that we are now able to substantially rejuvenate cells without changing their identity or functionality, says Reik. In previous studies, you would end up with a stem cell, which is not what youd want for therapy.

The technique may one day be useful in treating skin conditions, such as burns and ulcers. There is also the added bonus that the cells wouldnt be rejected by an individuals body, because they would be their own cells, says Gill.

So far, weve only tested this technique in skin cells. Were excited to see if we can translate it across other cell types, says Gill.

Journal reference: eLife, DOI: 10.7554/eLife.71624

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Anti-ageing technique makes skin cells act 30 years younger - New Scientist

Skin Stem Cells Comments Off on Anti-ageing technique makes skin cells act 30 years younger – New Scientist | April 15th, 2022

ASCE+ HRLVis the second product of ExoCoBio's professional aesthetic brand "ASCE+" whose first product "ASCE+ SRLV" for skin care is now widely recognized in a global market. ASCE+ HRLV is targeted for scalp rejuvenation and hair loss market and expected to rapidly expand its market share by introducing four effects: (1) scalp rejuvenation, (2) hair loss care, (3) improvement of hair anti-aging and (4) trouble prevention. They are designed to take care of both of scalp and hair regardless of age and gender.

According to the research conducted by Grand View Research (global market and research company), "the global hair and scalp care market size is valued at US$ 80.81 billion in 2020 and is anticipated to grow at a CAGR of 6.6% from 2021 to 2028." In recent years, there are growing concerns about the harmful effects of pollution, excessive use of hair products with chemicals, and the demand for nature-friendly products, whose market needs led to the launch of ASCE+ HRLV.

Dr. Iigo de Felipe, a Dermatologist with clinics in Barcelona and London, completed forthe last 2 years a clinical study for patients with scalp rejuvenation & hair loss using ASCE+ HRLV. When asked about his experience with the product, he said it is "better than other traditional treatments such as oral dutasteride, minoxidil or PRP" and praised its effectiveness affirming that it is "especially good in the frontal area of the scalp, an area where many other treatments usually fail". Dr. De Felipe also emphasized that "even though treatment is very effective for men, it is equally and sometimes even more effective for women too."

Over the past five years, ExoCoBio has made utmost efforts for R&D relating to skin, by using its patented technology "ExoSCRT" that is designed to isolate quality exosomes with excellent efficacy and to mass-produce exosomes (For more information on ExoSCRT, visit the following link: https://www.youtube.com/watch?v=ZOGQI8VuNOU). As a result, ExoCoBio became a global leader in exosome industry by obtaining 38 patents that are considered to be the strongest patent portfolio for exosomes in the world. Recently ExoCoBio successfully registered the patent "Composition for rejuvenating hair &, preventing hair aging comprising an exosome derived from stem cells as an active ingredient (Patent No. KR 10-2265875-0000)," which is the world first and unique idea to rejuvenate the hair color (i.e., hair returns to its original color).

"It is anticipated that the launch of ASCE+ HRLV will lead to expansion of ExoCoBio's share in the scalp rejuvenation and hair loss market as well as skin care market. In addition to the aesthetic product, ExoCoBio plans to develop a bio-medicine for hair loss through its R&D based on its innovative technology," stated Byong Cho, CEO of ExoCoBio (For HRLV technology, visit the following: https://www.youtube.com/watch?v=vkRcNCvNKAI).

References:https://www.grandviewresearch.com/industry-analysis/hair-care-markethttps://www.imcas.com/en/academy/show/11792/exosomes-in-treatment-of-androgenetic-alopecia-aga?connected=1

About ExoCoBio Inc. (www.exocobio.com)

ExoCoBio Inc. is the global leader who specializes in next generation exosome-based regenerative aesthetics, regenerative medicine, & immunotherapy. Currently ExoCoBio offers a series of exosome-based aesthetic & cosmetic products which are innovative and brand-new items in the regenerative aesthetics industry. Among them, ASCE+, EXOMAGE, and CELLTWEET are leading brands for skin rejuvenation, skin immune-modulation, and scalp rejuvenation, which have shown dramatic sales increase worldwide.

SOURCE ExoCoBio Inc.

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ExoCoBio launches "ASCE+ HRLV" for Scalp Rejuvenation and Hair Loss - PR Newswire

Skin Stem Cells Comments Off on ExoCoBio launches "ASCE+ HRLV" for Scalp Rejuvenation and Hair Loss – PR Newswire | April 15th, 2022

When a freak accident left mum-of-three Sam Bloom paralysed from the waist down, she sunk into a deep depression before finding comfort from an unlikely source.

Bloom stumbled across a baby magpie she called Penguin Bloom, and the bird soon became a member of her family - eventually helping to assist in her recovery.

Her book of the same name later became a movie, starring Australian actress Naomi Watts as Sam.

Watch The Morning Show on Channel 7 and stream it for free on 7plus >>

See Sam Bloom in the video player above

But that is far from the end of Blooms remarkable story.

She is both a world para-surf champion and disability advocate, fighting for a cure for spinal cord injuries.

When she joined The Morning Show, she started by discussing the impact of the film.

I think the best thing about the whole film and telling our story is just all the messages Ive received from people around the world, Bloom said.

It was on Netflix in South America and Europe and so on, and a lot of people have just said thank you because they dont feel so alone because it was a pretty honest account of when life doesnt turn out the way you thought it would.

Its nice to know that youre actually helping someone.

Bloom was an avid surfer before her accident, and her injury hasnt deterred her. She has twice taken out the world para-surf championship and recently returned from a surfing trip with her family in Yeppoon in north Queensland.

It was so much fun, the wave pool at Yeppoon is like a giant lake and its like it has this giant plunger in the middle and it sucks up, Bloom said.

Its a bit terrifying at first and then there are five different breaks - it is the best fun ever.

I feel super-free, kind of feel like my old self again, which is a nice feeling. Its the best.

Bloom also spoke about her work with Wings for Life World Run - the worlds largest running event in which thousands of people around the globe run simultaneously to raise money and awareness for spinal cord injury research.

The run is on May 8 at 9am in Sydney and the run starts all around the world at the same time, in a way were lucky that its not in the middle of the night in Sydney when it starts, Bloom said with a laugh.

Bloom explained the goal behind the run and her hopes for what it might ultimately achieve: funding vital research into spinal injuries.

Unfortunately its all about money, she said.

Thats the best thing about Wings for Life World Run, 100 per cent of the money raised goes straight to the research.

Its incredible, theyre doing a lot of research now with stem cells and neurostimulation.

I hope that theyll find a cure for spinal cord injuries. Can you imagine, theres millions of people around the world living with spinal cord injury and it breaks my heart when I see young people (affected).

Because I was 41 when I had my accident and I know how devastating it is, when you see young people and their journey is only just beginning.

Bloom revealed that, while her outlook is a lot more positive, she still struggles with living with her injury

I have good days and bad days, for sure, she said. To be honest, I hate being stuck in a wheelchair, Id do anything to be up and to be me again.

To help support the Wings for Life World Run please click here

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Still Blooming: Sams mission to raise money for spinal cord injury research - 7NEWS

Spinal Cord Stem Cells Comments Off on Still Blooming: Sams mission to raise money for spinal cord injury research – 7NEWS | April 15th, 2022

Scientists have created a stem cell treatment that might potentially lead to novel restorative therapies for those who have suffered a spinal cord damage.

Clinical trials have been hindered by limited stem cell viability and inability to replace injured spinal cord cells following spinal cord damage, despite its enormous promise for tissue healing.

Using a tailored method, this study establishes ground-breaking new territory by directing grafted neuronal stem cells to produce the specific kinds of spinal cord repair cells. It is critical that these newly generated cells survive and operate inside the host wounded spinal cord for a lengthy period of time following a spinal cord accident.

As a neurodegenerative ailment, spinal cord damage is a severe and expensive one, Karimi noted. She estimates that roughly 1,400 new occurrences of spinal cord injury occur annually in Canada, out of a total population of 86,000 people. Of them, 40% are all below the age of 45. It is anticipated that in 2019, the yearly cost of spine nerve lesion in Canada would be around $2.7 billion. She said that these expenses include medical treatment and hospitalizations, and also indirect expenses such as missed or decreased output.

Developing innovative restorative medicine therapies to enhance the standard of life for a wide group of people is an unfulfilled need in the field of spinal cord injury rehabilitation. This is exciting news for spinal cord injury sufferers, who have seen few advancements in treatment since the advent of stem cell research.

It will likely still be some time before this kind of treatment is available to patients, but we know that the researchers involved in this study are doing everything they can to advance neural stem cell transplantation therapies and bring them to a wider clinical application.

The study was published in The Journal of Neuroscience.

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Neural Stem Cell Therapy For Spinal Cord Injury To Tap Into The Potential Of Stem Cells - Optic Flux

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Lineage and Cancer Research UK Announce Completion of Patient Enrollment in Phase 1 Clinical Study of VAC2 for the Treatment of Non-small Cell Lung...

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SUNNYVALE, Calif., April 12, 2022 (GLOBE NEWSWIRE) -- BioCardia, Inc.[Nasdaq: BCDA], a developer of cellular and cell-derived therapeutics for the treatment of cardiovascular and pulmonary diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved the Company's Investigational New Drug (IND) application for BCDA-04, a proprietary allogeneic mesenchymal cell (MSC) population that is Neurokinin-1 receptor positive (NK1R+). This allows BioCardia to initiate its First-in-Human Phase I/II trial in adult patients recovering from Acute Respiratory Distress Syndrome (ARDS) due to COVID-19, with trial initiation expected in the third quarter of 2022.

The first part of the clinical trial will evaluate increasing doses of the NK1R+ MSCs and the optimal dose will be taken to Phase II in a randomized study in adult patients recovering from ARDS due to COVID-19. "This investigational cell therapy is administered intravenously (IV) and follows a significant body of compelling clinical results by NIH investigators and peer companies," said Ian McNiece, Ph.D., BioCardias Chief Scientific Officer. "After IV delivery, the cells migrate to the lungs for local therapeutic benefit. We expect the anti-inflammatory nature of these mesenchymal stem cells to have a positive impact in ARDS because of the interaction of the Neurokinin-1 receptors with Substance P, a neuropeptide that has long been known to be a primary mediator of inflammation in the lungs. Our goal is to help recovering patients with ARDS due to COVID-19 recover faster and more fully, while avoiding longer term respiratory issues."

"In addition to our critically important autologous cell therapies being studied for ischemic heart failure and chronic myocardial ischemia with refractory angina, the FDA's acceptance of this IND for patients recovering from ARDS is an important milestone in the development of our allogeneic mesenchymal stem cell therapy platform and validation for its potential to provide therapeutic benefit beyond the cardiovascular system," said Peter Altman, Ph.D., Chief Executive Officer. "Our off the shelf MSC platform may have significant advantages over others in clinical development for multiple indications because the MSCs express the biologically important NK1 receptor which binds Substance P. Our in-house clinical cell manufacturing is also expected to be an important strategic asset that enables rapid and cost-effective development."

About ARDS

Acute respiratory distress syndrome (ARDS) occurs when fluid builds up in the tiny, elastic air sacs (alveoli) in the lungs. The fluid keeps the lungs from filling with enough air, which means less oxygen reaches the bloodstream. This deprives organs of the oxygen they need to function. ARDS typically occurs in people who are already critically ill or who have significant injuries. Severe shortness of breath the main symptom of ARDS usually develops within a few hours to a few days after the precipitating injury or infection. Many people who develop ARDS don't survive. The risk of death increases with age and severity of illness. Of the people who do survive ARDS, some recover completely while others experience lasting damage to their lungs1. Based on preliminary clinical reports on COVID-19, respiratory failure complicated by ARDs is the leading cause of death for COVID-19 patients.2 Despite multiple clinical studies, no pharmacological treatments have proven effective for ARDS.3, 4

About BioCardia

BioCardia, Inc., headquartered in Sunnyvale, California, is developing cellular and cell-derived therapeutics for the treatment of cardiovascular and pulmonary disease. CardiAMP autologous and NK1R+ allogeneic cell therapies are the Companys biotherapeutic platforms that enable four product candidates in clinical development. The CardiAMP Cell Therapy Heart Failure Trial investigational product has been granted Breakthrough designation by the FDA, has CMS reimbursement, and is supported financially by the Maryland Stem Cell Research Fund. The CardiAMP Chronic Myocardial Ischemia Trial also has CMS reimbursement. For more information visit:www.BioCardia.com.

FORWARD LOOKING STATEMENTS

This press release contains forward-looking statements that are subject to many risks and uncertainties. Forward-looking statements include, among other things, initiation of our BCDA-04 clinical trial, and the mechanism of action and ease of administration of our NK1R+ MSC therapy.

We may use terms such as believes, estimates, anticipates, expects, plans, intends, may, could, might, will, should, approximately or other words that convey the uncertainty of future events or outcomes to identify these forward-looking statements. Although we believe that we have a reasonable basis for each forward-looking statement contained herein, we caution you that forward-looking statements are not guarantees of future performance and that our actual results may differ materially from the forward-looking statements contained in this press release. As a result of these factors, we cannot assure you that the forward-looking statements in this press release will prove to be accurate. Additional factors that could materially affect actual results can be found in BioCardias Form 10-K filed with the Securities and Exchange Commission on March 29, 2022, under the caption titled Risk Factors. BioCardia expressly disclaims any intent or obligation to update these forward-looking statements, except as required by law.

_________________________________________________________________________________________________________

Media Contact:Anne Laluc, MarketingEmail:alaluc@BioCardia.comPhone: 650-226-0120

Investor Contact:David McClung, Chief Financial OfficerEmail:dmcclung@BioCardia.comPhone: 650-226-0120

(1)MayoClinic.Org

(2)Rajagopal K, Keller SP, Akkanti B, et al. Advanced pulmonary and cardiac support of COVID-19 patients, emerging recommendations from ASAIOa living working document. Circ Heart Fail. 2020 May;13(5).

(3)Thompson BT, Chambers RC, Liu KD (2017) Acute respiratory distress syndrome. N Engl J Med 377(19):19041905.

(4)3. Group RC, Horby P, Lim WS et al (2020) Dexamethasone in hospitalized patients with Covid-19preliminary report. N Engl J Med.

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BioCardia Announces FDA Approval of Its IND for NK1R+ Mesenchymal Stem Cells for the Treatment of Patients Recovering from Acute Respiratory Distress...

Cardiac Stem Cells Comments Off on BioCardia Announces FDA Approval of Its IND for NK1R+ Mesenchymal Stem Cells for the Treatment of Patients Recovering from Acute Respiratory Distress… | April 15th, 2022

Early findings from the phase 1/2a TEM-GBM study presented at the 2022 AACR Annual Meeting displayed potential of temferon to affect the tumor microenvironment of glioblastoma.

Immune system activation and tumor microenvironment alteration were effects observed in patients with glioblastoma treatment with temferon, a genetically modified Tie2-expressing monocyte (TEM) targeting interferon-2 (IFN2), according to early findings of the phase 1/2a TEM-GBM study (NCT03866109) presented in a poster at the American Association for Cancer Research (AACR) 2022 Annual Meeting.

These results provide the initial evidence for on-target activity of Temferon in GBM, said Bernard Gentner, MD, study coauthor and the leader of the translational stem cell and leukemia research unit at San Raffaele Telethon Institute for Gene Therapy in Milan, Italy.

Temferon is an investigational advanced therapy consisting of autologous CD34+-enriched hematopoietic stem and progenitor cells exposed to transduction with a lentiviral vector, driving myeloid-specific IFN2 expression. Genetically modified TEMs target IFN2 expression in the GBM tumor microenvironment.

In order to guarantee stable delivery of genetically engineered TEMs into the tumor, we transduce hematopoietic stem and progenitor cells with a lentiviral vector carrying the IFNa2 transgene transcriptionally regulated by the Tie2 promoter and by post transcriptional elements that guarantee that the transgene is expressed only in myeloid cells that are recruited into the tumor, Gentner said.

TEM-GBM is an open-label, dose-escalation study evaluating the safety and efficacy of Temferon in up to 21 newly diagnosed patients with GBM harboring an unmethylated MGMT promoter. Following surgical resection, up to 15 patients were assigned to 1 of 3 escalating doses of Temferon and 1 of 2 different conditioning regimens in part A of the trial. In Part B, 6 more patients will receive a single dose of Temferon at the recommended phase 2 dose.

Following completion of radiotherapy, patients received a conditioning regimen consisting of carmustine (BCNU) and thiotepa (Tepadina) in cohorts 1 to 4 or busulfan (Busulfex) and thiotepa in cohort 5 prior to administration of Temferon.

In-patient monitoring occurs until hematological recovery, then patients will undergo regular follow-up for up to 720 days. At that point, patients are invited to participate in a long term follow-up study for an additional 6 years.

Eligible adults aged 18 to 70 years must have an ECOG performance score of 0 to 1, a Karnofsky performance score greater than 70%, and adequate cardiac, renal, hepatic, and pulmonary function. Patients with active autoimmune disease or who have received any oral or parenteral chemotherapy or immunotherapy within 2 years of screening are excluded.

The primary end points of the study are Temferon engraftment over the first 90 days, proportion of patients achieving hematologic recovery 30 days after autologous stem cell transplantation, and short-term tolerability of Temferon as defined by stable blood counts, absence of cytopenias, absence of significant organ toxicities greater than grade 2, and absence of Replication Competent Lentivirus.

By the October 15, 2021, data cutoff, the median follow-up was 267 days (range: 60-749). Patients in cohorts 1 to 3 received a dose 0.5-2.0 x 106/kg Temferon with an average vector copy number of 0.70 and a transduction efficiency of 54%. Those in cohorts 4 and 5 received 2.0 x 106/kg Temferon with an average vector copy number of 0.77 and a transduction efficiency of 49%.

Investigators observed increasing proportions of Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood and bone marrow cells, reaching up to 30% at 1 month in the highest treatment cohort (2.0 x 106/kg). Those differentiated cells persisted at lower levels for up to 18 months.

All patients showed in vivo Temferon engraftment, Gentner said. Engraftment was highest at 1 month, and in many patients resembled pretty much the input fraction. Engraftment then decreased, stabilizing at 3 to 6 months around 10%.

Despite the significant proportion of engineered cells, only very low-medium concentrations of interferon alpha were detected in the plasma and in the cerebral spinal fluid, indicating a tight regulation of the vector expression.

Gentner added that Temferon did not delay hemopoietic recovery, and neutrophil and platelet engraftment were similar to standard autologous stem cell procedure.

Investigators did not detect any dose limiting toxicities. Gentner said that, so far, adverse events have been related to progression or the transplant procedure, not to the IFN2 itself.

Gentner B, Finocchiaro G, Farina F, et al. Genetically modified Tie-2 expressing monocytes target IFN-2 to the glioblastoma tumor microenvironment (TME): Preliminary data from the TEM-GBM Phase 1/2a study. Poster presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 5213.

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Evidence Shows Novel Temferon May Have Activity in Glioblastoma - Cancer Network

Cardiac Stem Cells Comments Off on Evidence Shows Novel Temferon May Have Activity in Glioblastoma – Cancer Network | April 15th, 2022

April 9 (Reuters) - The first all-private team of astronauts ever launched to the International Space Station (ISS) were welcomed aboard the orbiting research platform on Saturday to begin a weeklong science mission hailed as a milestone in commercial spaceflight.

Their arrival came about 21 hours after the four-man team representing Houston-based startup company Axiom Space Inc lifted off on Friday from NASA's Kennedy Space Center, riding atop a SpaceX-launched Falcon 9 rocket.

The Crew Dragon capsule lofted into orbit by the rocket docked with the ISS at about 8:30 a.m. EDT (1230 GMT) on Saturday as the two space vehicles were flying roughly 250 miles (420 km) above the central Atlantic Ocean, a live webcast of the coupling from the National Aeronautics and Space Administration showed.

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The final approach was delayed for about 45 minutes by a technical glitch with a video feed used to monitor the capsule's rendezvous with the ISS, but it otherwise proceeded smoothly.

The multinational Axiom team, planning to spend eight days in orbit, was led by retired Spanish-born NASA astronaut Michael Lopez-Alegria, 63, the company's vice president for business development.

His second-in-command was Larry Connor, a real estate and technology entrepreneur and aerobatics aviator from Ohio designated as the mission pilot. Connor is in his 70s, but the company did not provide his precise age.

Rounding out the Ax-1 crew were investor-philanthropist and former Israeli fighter pilot Eytan Stibbe, 64, and Canadian businessman and philanthropist Mark Pathy, 52, both serving as mission specialists.

With docking achieved, it took nearly two hours for the sealed passageway between the space station and crew capsule to be pressurized and checked for leaks before hatches were opened to allow the newly arrived astronauts to come aboard the ISS.

The Ax-1 team was welcomed by all seven of the regular, government-paid crew members already occupying the space station: three American astronauts, a German astronaut from the European Space Agency and three Russian cosmonauts.

The NASA webcast showed the four smiling Axiom astronauts, dressed in navy blue flight suits, floating headfirst, one by one, through the portal into the space station, warmly greeted with hugs and handshakes by the ISS crew.

Lopez-Alegria later pinned astronaut wings onto the uniforms of the three spaceflight rookies of his Axiom team -- Connor, Stibbe and Pathy -- during a brief welcome ceremony.

Stibbe is now the second Israeli to fly to space, after Ilan Ramon, who perished with six NASA crewmates in the 2003 space shuttle Columbia disaster.

SCIENCE FOCUSED

The new arrivals brought with them two dozen science and biomedical experiments to conduct aboard ISS, including research on brain health, cardiac stem cells, cancer and aging, as well as a technology demonstration to produce optics using the surface tension of fluids in microgravity.

The mission, a collaboration among Axiom, Elon Musk's rocket company SpaceX and NASA, has been touted by all three as a major step in the expansion of space-based commercial activities collectively referred to by insiders as the low-Earth orbit economy, or "LEO economy" for short. read more

NASA officials say the trend will help the U.S. space agency focus more of its resources on big-science exploration, including its Artemis program to send humans back to the moon and ultimately to Mars.

While the space station has hosted civilian visitors from time to time, the Ax-1 mission marks the first all-commercial team of astronauts sent to ISS for its intended purpose as an orbiting research laboratory.

The Axiom mission also stands as SpaceX's sixth human spaceflight in nearly two years, following four NASA astronaut missions to the space station and the Inspiration 4 launch in September that sent an all-civilian crew into orbit for the first time. That flight did not dock with the ISS.

Axiom executives say their astronaut ventures and plans to build a private space station in Earth orbit go far beyond the astro-tourism services offered to wealthy thrill-seekers by such companies as Blue Origin and Virgin Galactic (SPCE.N), owned respectively by billionaire entrepreneurs Jeff Bezos and Richard Branson.

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Reporting by Steve Gorman in Los Angeles; Editing by Angus MacSwan, Daniel Wallis and Jonathan Oatis

Our Standards: The Thomson Reuters Trust Principles.

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Space station's first all-private astronaut team welcomed aboard orbiting platform - Reuters

Cardiac Stem Cells Comments Off on Space station’s first all-private astronaut team welcomed aboard orbiting platform – Reuters | April 15th, 2022

Courtesy of Pavlo Gonchar/SOPA Images/LightRocket via Getty Images

Drug pricing watchdog ICER, the Institute for Clinical and Economic Review, issued a draft report on bluebird bios gene therapy betibeglogene autotemcel for beta-thalassemia. Despite the proposed price tag of $2.1 million, ICERs not-yet-finalized report supports the therapys cost-effectiveness. This is good news for the recently beleaguered company.

Gene therapies are typically designed to cure a disease by replacing or fixing a damaged gene. Bluebirds therapy, which is listed under the brand name Zynteglo, had been approved in Europe and the UK, where its price is around $1.7 million (U.S.). However, the company pulled the therapy off the market in Europe over what it called a hostile pricing and reimbursement environment.

On April 5, bluebird bio announced it was beginning a comprehensive restructuring in hopes of cutting $160 million in costs over the next two years. It planned to re-focus on near-term catalysts, which include Zynteglo in the U.S., gene therapy for cerebral adrenoleukodystrophy (eli-cel) and a potential biologics license application (BLA) for lovotibeglogene autotemcel (lovo-cel) gene therapy for sickle cell disease. The BLA application is planned for 2023, while the U.S. regulatory decisions are expected this year. The PDUFA date for Zynteglo is Aug.19, 2022, and Sept. 16, 2022, for eli-cel.

As part of the restructuring, the company is cutting its workforce by about 30%.

ICER recommendations arent binding, but they have influence. If ICER says a drug is overpriced, it provides ammunition for payers, such as Medicare and insurers, to push back against proposed prices.

Gene therapies are very expensive. For example,Novartis Zolgensma, the one-time gene therapy onasemnogene abeparvovec for spinal muscular atrophy (SMA), is generally viewed as the most expensive drug with a price tag of $2.1 million. On the other hand, as an apparent cure for a disease that kills children by the age of two, it is very rare. The argument for these therapies, aside from their curative potential for otherwise incurable diseases, is that over the life of the patient, they are cost-effective.

Novartis and Spark Therapeuticss gene therapy Luxturna (voretigene neparvovec) runs about $850,000 per patient in the U.S. The therapy is for inherited retinal dystrophy with RPE65 mutations. It is typically diagnosed in childhood and eventually causes almost total blindness, and the therapy is essentially a cure.

Beta thalassemia is a genetic disease that impairs the ability of red blood cells to manufacture hemoglobin, the molecule in the body that carries oxygen. There are about 40,000 newly diagnosed cases in children each year around the world. People with the most severe form of it develop life-threatening anemia around four to six months of age and have to receive monthly blood transfusions and other treatments, such as iron-chelating drugs. The only other potential cure is hematopoietic stem cell transplantation (HSCT) but requires a donor with a matching human leukocyte antigen (HLA) profile within the appropriate age range.

Bluebirds Zynteglo appears to be another option for a cure, although how long the therapys effects last is something of an open question. The ICER report noted the uncertainties, but concluded that the evidence suggests that beti-cel provides net health benefits to patients with TDT.

The ICER report indicated, per Managed Healthcare Executive, that "patients could be treated without reaching the potential budget impact threshold at three prices (about $1.85 million, $2.11 million and $2.38 million per course of treatment). This analysis was done at several prices to document the percentage of patients who could be treated without crossing a potential budget impact threshold that is aligned with the overall growth in the U.S. economy.

In Phase III trials, 89% of patients who received the therapy became transfusion independent, and in Phase I/II and III trials, those patients remained transfusion-free for at least 42 months. In general, side effects were mild and no deaths were reported. In December 2021, bluebird presented data at the American Society of Hematology meeting from a long-term study (LTF-303) that showed adult and pediatric patients with beta-thalassemia who required regular red blood cell transfusions can produce normal or near-normal levels of total hemoglobin and remain transfusion-free with stable iron markers up to seven years after receiving beti-cel.

A 2017 study published in Blood found that on average, beta-thalassemia patients required 17 transfusions per year, 23 days apart. Mean total healthcare costs for the patients were $128,062, plus or minus $62,260 per year. Total costs were primarily driven by chelation and transfusion costs.

Although the severity of the disease varies, a 2009 study found that people with beta-thalassemia major often die from cardiac complications of iron overload by 30 years of age," making bluebird's new therapy, if it is successful, vital for these patients.

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Drug Price Watchdog Calls Bluebird Bio's $2.1 Million Gene Therapy Cost-Effective - BioSpace

Cardiac Stem Cells Comments Off on Drug Price Watchdog Calls Bluebird Bio’s $2.1 Million Gene Therapy Cost-Effective – BioSpace | April 15th, 2022

The addition of the innate cell engager AMF13 to preactivated and expanded natural killer (NK) cells may represent an effective treatment for pretreated patients with advanced lymphoma, according to findings from a phase 1/2 study (NCT04074746) that were presented during the 2022 AACR Annual Meeting. 1

Results showed that patients experienced a median overall response rate (ORR) of 89.5% (n = 17/19). Overall, 10 patients experienced complete responses (CRs) and 7 experienced partial responses (PRs).2

Lead author Yago Nieto, MD, PhD, a professor of medicine in the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center, in Houston, discussed the findings during a press conference during the meeting. He said the study team was pleasantly surprised by the quality of tumor responses in patients with resistant lymphomas.

This is the first clinical trial using off the shelf cord blood-derived cytokine-induced memory-likeex vivoexpanded NK cells precomplexed with the innate cell engager AMF13 construct to treat patients with CD30-positive relapsed/refractory Hodgkin lymphoma, he said. We saw very encouraging activity in this population of very heavily pretreated patients.

The current standard of care for relapsed CD30-positive lymphomas is brentuximab vedotin (Adcetris), an antibody-drug conjugate that delivers a toxic cytoskeleton destabilizing agent to cells expressing CD30. However, not all these lymphomas respond to brentuximab vedotin. When that treatment fails, those tumors then become extremely resistant to killing and patients are left with very few effective therapeutic options.

To address the problem, investigators enrolled 22 patients with relapsed or refractory CD30+ lymphoma into this single-center phase 1/2 trial, 20 of whom were diagnosed with Hodgkin lymphoma (HL). All had active progressive disease at enrollment, and none received bridging therapy. Patients were heavily pretreated, with a median of 7 (range, 1-14) prior lines of therapy. Nine underwent autologous stem cell transplantation (SCT) and 5 received allogeneic SCT.

Eligible patients had relapsed/refractory CD30-positive classical HL, B-cell non-Hodgkin lymphoma, anaplastic large-cell lymphoma, or peripheral T-cell lymphoma that was refractory or intolerant to brentuximab vedotin. They needed to have an ECOG performance status of 2 or below, and adequate renal, hepatic, pulmonary, and cardiac function.

The median age was 40 years (range, 20-75). Most patients were white (68.2%) and male 68.1%).

Patients receive 2 cycles of fludarabine/cyclophosphamide, followed by AFM13-CB NK cells at 3 dose levelsDL1 (106NK/gg), DL2 (107NK/kg), and DL3 (108NK/kg)on day 0 plus 3 weekly intravenous infusions of 200 mg AFM13, a CD30/CD16A bispecific antibody. Nineteen patients completed both planned cycles of treatment.

Nieto and colleagues isolated NK cells from cord blood, then used a mixture of cytokines to activate the cells into a memory-like state, making them more persistent and effective. They then expanded the cells in culture and complexed them with AFM13.

At a median follow-up of 11 months, progression-free survival (PFS) and overall survival (OS) rates across all 3 dose levels were 52% and 81%, respectively. Across all dose levels, 53% of patients experienced CR and 37% had PR. Eleven percent had progressive disease.

Expansion of NK cells occurred immediately after infusion and persisted for 3 weeks.

Investigators established DL3 as the recommend phase 2 dose (RP2D). All 13 (100%) patients treated at this dose level responded to therapy, including eight CRs (62%).Five of those patients were in CR after cycle 1, and 3 additional patients converted from PR to CR after cycle 2, Nieto added.

The median PFS was 67% and the median OS was 93% in the RP2D population.

Investigators did not record any cytokine release syndrome or graft vs host disease (GVHD), or neurotoxicity. Our preliminary results show an excellent tolerability profile, Nieto said.

There was no instance of infusion-related reactions (IRRs) associated with AFM13-NK cells across 40 infusions. There was 1 instance of grade 3 IRR and 4 grade 2 IRRs in 108 infusions of AFM13 alone. Investigators observed no dose limiting toxicities.

Never before in mankind have we seen this approach, really leading to pretty staggering results, Timothy Yap, MBBS, PhD, FRCP, a medical oncologist and associate director of translational research in the Institute for Personalized Cancer Therapy at the University of Texas MD Anderson Cancer Center, said. Everyone can see for themselves how impressive these results are. In addition to that, the actual tolerability profile is truly excellent with no instances of cytokine release syndrome, no neurotoxicity, no GVHD. Truly, truly impressive.

References

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Adding Bispecific Antibody to Natural Killer Cells May Be Effective in Heavily Pretreated Lymphoma - http://www.oncnursingnews.com/

Cardiac Stem Cells Comments Off on Adding Bispecific Antibody to Natural Killer Cells May Be Effective in Heavily Pretreated Lymphoma – www.oncnursingnews.com/ | April 15th, 2022

The use of human bone marrow mesenchymal stem cells (hBMSCs) to regenerate and repair bone tissue defects is a complex research field of bone tissue engineering; nevertheless, it is a hot topic. One of the biggest problems is the limited survival and osteogenic capacity of the transplanted cells within the host tissue. Even for hBMSCs with their low immunogenicity, the body will still cause a local immune-inflammatory response directed against the allogeneic cells and thereby reduce the activity of the transplanted cells. Even in the case of successful transplantation, the lack of vascularization at the transplantation site makes it difficult for the transplanted cells to exchange nutrients and metabolic wastes that ultimately affects bone regeneration. In this study, we covalently modified alginate with RGD and QK peptides that were injected subcutaneously into immunocompetent mice. Histological analysis, as well as ELISA techniques, proved that this method is able to provide bioactive stem cell transplant beds containing functionalized biomaterials and vascularized surrounding tissues. Inflammation-related factors, such as IL-2, IL-6, TNF-, and IFN-, around the cell graft beds decreased with time and were lowest at the second week. Then, the hBMSCs were injected into the cell transplantation beds intended to form vascularized bonelike tissues that were evaluated by micro-computed tomography (Micro CT), histological, and immunohistochemical analyses. The results showed that the expression of osteogenesis-related proteins RUNX2, COL1A1, and OPN, as well as the expression of angiogenic factor vWF and cartilage-related protein COL2A1 were significantly upregulated in the hBMSC-derived osteogenic tissue. These results suggest that the stem cell transplantation strategy by constructing bioactive cell transplant beds is effective to enhance the bone regeneration capacity of hBMSCs and holds great potential in bone tissue engineering.

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Strategy of Stem Cell Transplantation for Bone Regeneration with Functionalized Biomaterials and Vascularized Tissues in Immunocompetent Mice -...

Bone Marrow Stem Cells Comments Off on Strategy of Stem Cell Transplantation for Bone Regeneration with Functionalized Biomaterials and Vascularized Tissues in Immunocompetent Mice -… | April 3rd, 2022

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A breakthrough made by Australian researchers might change the way doctors treat a broken or missing bone. Turns out stem cells can turn into bone if certain conditions are met.

Normally, bone can be made only of mesenchymal stem cells (MSCs) which are biologically found in the bone marrow.

Extracting them from there is a difficult and painful procedure while doing so at scale is beyond tricky.

But this could change any moment now after Australian researchers found that stem cells can be converted into bone when a certain type of sound waves are used.

Tests had previously shown that low frequency vibrations were great at inducing cell differentiation but the process took over a week and the results were mixed at best.

Nobody had bothered to look into high frequency sound waves until now. RMIT researchers took a microchip capable of dispersing sound waves in the Mhz range and turned it at MSCs in silicon oil on a culture plate.

The team noticed that after exposing the cells to 10MhZ signals for 10 minutes daily for five days, the markers indicating the bone conversion appeared.

We can use the sound waves to apply just the right amount of pressure in the right places to the stem cells, to trigger the change process, said Leslie Yeo, co-lead researcher on the study. Our device is cheap and simple to use, so could easily be upscaled for treating large numbers of cells simultaneously vital for effective tissue engineering.

This discovery, detailed in the journalSmall, eliminates the need of drugs to make stem cells behave this way. Moreover, the MSCs can be pulled from a variety of places, like fast tissue, not just bone marrow.

By injecting them into the body in case of an injury or disease, they can start working on a new bone faster and more efficient.

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Stem Cells Turn Into Bone When Sound Waves Are Near - TechTheLead

Bone Marrow Stem Cells Comments Off on Stem Cells Turn Into Bone When Sound Waves Are Near – TechTheLead | April 3rd, 2022

Jasper Therapeutics

REDWOOD CITY, Calif., March 31, 2022 (GLOBE NEWSWIRE) -- Jasper Therapeutics, Inc. (NASDAQ: JSPR), a biotechnology company focused on hematopoietic cell transplant therapies, today announced that updated data from the Companys ongoing study of JSP191 as single agent conditioning prior to allogeneic hematopoietic stem cell (HSC) re-transplant in patients with severe combined immunodeficiency (SCID) has been accepted for presentation as a late-breaking poster at the 2022 Clinical Immunology Society (CIS) Annual Meeting, to be held in Charlotte, North Carolina from March 31 to April 3, 2022.

Title: Update: Single-Agent Conditioning with Anti-CD117 Antibody JSP191 Shows Donor Engraftment, Nave Lymphocyte Production, and Clinical Benefit in Patients with Severe Combined Immunodeficiency (SCID)Date and Time: Friday, April 1, 2022, 1:00-2:00 p.m. ET

This updated data indicates that JSP191 at 0.6mg/kg can deplete blood stem cells, leading to long-term donor cell engraftment, immune reconstitution which positively affects the clinical status of SCID patients who suffer from poor T cell and negligible B cell immunity because they failed their first transplant, said Wendy Pang, MD, Ph.D., Senior Vice President of Research and Translational Medicine of Jasper Therapeutics. This population of SCID patients is largely without treatment options and rely on supportive therapies like life long IVIG to provide some level of immune protection. JSP191 based conditioning may provide these patients with the best chance of a safe and successful transplant and reconstituted immune system.

CIS attendees are the primary caregivers for the immune deficient patient population, we are pleased to be able to present this data at the 2022 CIS annual meeting, Ronald Martell, CEO of Jasper. We believe that with our successful clinical efforts, we are one step closer, and uniquely positioned to deliver a targeted non-genotoxic conditioning agent to patients with SCID.

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About JSP191

JSP191 is a humanized monoclonal antibody in clinical development as a conditioning agent that blocks stem cell factor receptor signaling leading to clearance of hematopoietic stem cells from bone marrow, creating an empty space for donor or genetically modified transplanted stem cells to engraft. To date, JSP191 has been evaluated in more than 100 healthy volunteers and patients. Three clinical trials for myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), severe combined immunodeficiency (SCID) and Fanconi anemia are currently enrolling. The Company plans a new study of JSP191 as a second-line therapeutic in lower risk MDS patients in 2022 as well as to a pivotal study in MDS/AML transplant in early 2023. Enrollment in additional studies are planned in patients with sickle cell disease, chronic granulomatous disease and GATA2 MDS who are undergoing hematopoietic cell transplantation.

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, an anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing hematopoietic cell transplantation. It is designed to enable safer and more effective curative allogeneic hematopoietic cell transplants and gene therapies. In parallel, Jasper Therapeutics is advancing its preclinical mRNA engineered hematopoietic stem cell (eHSC) platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

Forward-Looking Statements

Certain statements included in this press release that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements are sometimes accompanied by words such as believe, may, will, estimate, continue, anticipate, intend, expect, should, would, plan, predict, potential, seem, seek, future, outlook and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding the potential long-term benefits of hematopoietic stem cells (HSC) engraftment following targeted single-agent JSP191 conditioning in the treatment of severe combined immunodeficiency (SCID) and Jaspers ability to potentially deliver a targeted non-genotoxic conditioning agent to patients with SCID. These statements are based on various assumptions, whether or not identified in this press release, and on the current expectations of Jasper and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on by an investor as, a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Jasper. These forward-looking statements are subject to a number of risks and uncertainties, including general economic, political and business conditions; the risk that the potential product candidates that Jasper develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all; risks relating to uncertainty regarding the regulatory pathway for Jaspers product candidates; the risk that clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release; the risk that Jasper will be unable to successfully market or gain market acceptance of its product candidates; the risk that Jaspers product candidates may not be beneficial to patients or successfully commercialized; patients willingness to try new therapies and the willingness of physicians to prescribe these therapies; the effects of competition on Jaspers business; the risk that third parties on which Jasper depends for laboratory, clinical development, manufacturing and other critical services will fail to perform satisfactorily; the risk that Jaspers business, operations, clinical development plans and timelines, and supply chain could be adversely affected by the effects of health epidemics, including the ongoing COVID-19 pandemic; the risk that Jasper will be unable to obtain and maintain sufficient intellectual property protection for its investigational products or will infringe the intellectual property protection of others; and other risks and uncertainties indicated from time to time in Jaspers filings with the SEC. If any of these risks materialize or Jaspers assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. While Jasper may elect to update these forward-looking statements at some point in the future, Jasper specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Jaspers assessments of any date subsequent to the date of this press release. Accordingly, undue reliance should not be placed upon the forward-looking statements.

Contacts:John Mullaly (investors)LifeSci Advisors617-429-3548jmullaly@lifesciadvisors.com

Jeet Mahal (investors)Jasper Therapeutics650-549-1403jmahal@jaspertherapeutics.com

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Jasper Therapeutics to Present Updated Data on JSP191 Conditioning in SCID Patients at the 2022 Clinical Immunology Society Annual Meeting - Yahoo...

Bone Marrow Stem Cells Comments Off on Jasper Therapeutics to Present Updated Data on JSP191 Conditioning in SCID Patients at the 2022 Clinical Immunology Society Annual Meeting – Yahoo… | April 3rd, 2022

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The noticeable players in the worldwide Rheumatoid Arthritis Stem Cell Therapy are

Mesoblast Ltd., Roslin Cells, Regeneus Ltd, ReNeuron Group plc, International Stem Cell Corporation, TiGenix and others

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By Product Type (Allogeneic Mesenchymal Stem Cells, Bone Marrow Transplant and Adipose Tissue Stem Cells)

By End-User (Hospitals, Ambulatory Surgical Centers and Specialty Clinics)

By Region (North America, Europe, Asia Pacific, Latin America, and Middle East & Africa)

Mesoblast Ltd., Roslin Cells, Regeneus Ltd, ReNeuron Group plc, International Stem Cell Corporation, TiGenix and others

Promising Regions & Countries Mentioned In The Rheumatoid Arthritis Stem Cell Therapy Report:

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Segmentation Overview:

By Product Type (Allogeneic Mesenchymal Stem Cells, Bone Marrow Transplant and Adipose Tissue Stem Cells)

By End-User (Hospitals, Ambulatory Surgical Centers and Specialty Clinics)

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Rheumatoid Arthritis Stem Cell Therapy Market Assessment, With Major Top Companies Analysis, Geographic Analysis, Growing Opportunities Data By...

Bone Marrow Stem Cells Comments Off on Rheumatoid Arthritis Stem Cell Therapy Market Assessment, With Major Top Companies Analysis, Geographic Analysis, Growing Opportunities Data By… | April 3rd, 2022

This article was originally published here

Bioengineered. 2022 Apr;13(4):8382-8395. doi: 10.1080/21655979.2022.2036891.

ABSTRACT

The exosomes (Exo) had always been considered as transport vectors for microRNA (miRNA). An increasing number of data had clarified the influence of Exo on the cell progression of non-small cell lung cancer (NSCLC). Nevertheless, its specific mechanism had not yet been verified. This work was to explore the potential mechanism of Exo-derived miR-631 targeting and regulating E2F family of transcription factor 2 (E2F2) to repress the malignant behavior of NSCLC cells. Test of microRNA (miR)-631 and E2F2 in NSCLC was performed. BMSCs-Exo that altered miR-631 was co-cultured with NSCLC cells. Detection of the cloning and progression of NSCLC cells was performed. Testification of the targeting of miR-631 with E2F2 was conducted. In vivo experiments were performed to verify the results in vitro. In short, elevation of miR-631 Exo repressed the advancement and phosphatidylinositol 3-kinase/Akt activation of NSCLC cells, while silence of miR-631 was in the opposite. In terms of mechanism, miR-631 exerted the influence via targeting E2F2. The coincident results were obtained in animal models. In brief, BMSC-Exo mediated E2F2 via delivering miR-631 to NSCLC cells to modulate the malignant behavior of NSCLC.

PMID:35353027 | DOI:10.1080/21655979.2022.2036891

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MicroRNA-631 deriving from bone marrow mesenchymal stem cell exosomes facilitates the malignant behavior of non-small cell lung cancer via modulating...

Bone Marrow Stem Cells Comments Off on MicroRNA-631 deriving from bone marrow mesenchymal stem cell exosomes facilitates the malignant behavior of non-small cell lung cancer via modulating… | April 3rd, 2022

Abstract:

Background:

Objective:To observe the effect of H2O2 induced oxidative stress on autophagy and apoptosis of human bone marrow mesenchymal stem cells (hBMSCs).

Method: The hBMSCs were separated and cultured by density gradient centrifugation combined with adherence method. They were divided into blank group (with medium only), 3-MA (autophagy inhibitor) pretreatment group (with 2 ml of 5 mM 3-MA medium), H2O2 Intervention group (add 2ml medium containing 0.05mM H2O2), H2O2+3-MA treatment group (add 2ml medium containing 5mM 3-MA, then add 2ml medium containing 0.05mM H2O2). DCFH-DA staining was used to detect cellular reactive oxygen species (ROS) levels,and CCK-8 analysis was used to detect the effects of different concentrations (0,50,100,200,400mol/L) of H2O2 on the proliferation of hBMSCs; Monodansylcadaverine(MDC) Fluorescent amine probe staining, Lysosome Red Fluorescent Probe (Lyso-Tracker Red) staining to observe the level of autophagy; Immunofluorescence staining to detect the expression of LC3A/B; Flow cytometry (Annexin V/PI) to detect cell apoptosis Circumstances; Protein chip detection of autophagy-related proteins; Western blot detection of Beclin1, mTOR, p-mTOR, LC3A/B, and Cleaved caspase-3 protein expression.

Result: After treating hBMSCs with different concentrations of H2O2 (0,50,100,200,400mol) for 24h ,48h, and 72h, with the increase of H2O2 concentration, the cell proliferation ability decreased; while with the extension of time, the cell proliferation ability increased not significantly; 50mol cell proliferation ability is the strongest. Compared with the blank group and 3-MA group, the H2O2 intervention group increased the level of intracellular ROS, increased autophagosomes, and significantly decreased the apoptosis rate; up-regulated Beclin1, mTOR, LC3A/B and Cleaved caspase-3 protein expression, and down-regulated p-mTOR Protein expression level. Compared with the autophagy inhibitor 3-MA group, the H2O2+3-MA group increased the level of intracellular ROS, increased autophagosomes, and did not significantly increase the apoptosis rate; up-regulated the protein expression of Beclin1, mTOR, LC3A/B and Cleaved caspase-3 Down-regulate the expression of p-mTOR protein.

Conclusion: H2O2 can induce hMSCs to produce oxidative stress response. Under oxidative stress conditions, hMSCs can promote protective autophagy and reduce cell apoptosis or the level of apoptosis caused by excessive autophagy.

See more here:
Effect of oxidative stress-induced autophagy on proliferation and apoptosis of hMSCs - Newswise

Bone Marrow Stem Cells Comments Off on Effect of oxidative stress-induced autophagy on proliferation and apoptosis of hMSCs – Newswise | April 3rd, 2022