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• W2984490538 abstract "Although the clinical outcomes of cell therapy trials have not met initial expectations, emerging evidence suggests that injury-mediated tissue damage might benefit from the delivery of cells or their secreted products. Pluripotent stem cells (PSCs) are promising cell sources primarily because of their capacity to generate stage- and lineage-specific differentiated derivatives. However, they carry inherent challenges for safe and efficacious clinical translation. This Review describes completed or ongoing trials of PSCs, discusses their potential mechanisms of action, and considers how to address the challenges required for them to become a major therapy, using heart repair as a case study. Although the clinical outcomes of cell therapy trials have not met initial expectations, emerging evidence suggests that injury-mediated tissue damage might benefit from the delivery of cells or their secreted products. Pluripotent stem cells (PSCs) are promising cell sources primarily because of their capacity to generate stage- and lineage-specific differentiated derivatives. However, they carry inherent challenges for safe and efficacious clinical translation. This Review describes completed or ongoing trials of PSCs, discusses their potential mechanisms of action, and considers how to address the challenges required for them to become a major therapy, using heart repair as a case study. Whereas the treatment of most diseases has long relied on two main pillars, i.e., drugs and interventional procedures, biotherapies have emerged as a potential third player over the past two decades. Among them, cells (which do not always fulfill the criterion of “stemness” despite this common way of naming them) are receiving a continued interest. This is largely because they feature a major disruption from conventional therapies in that they do not only aim at relieving symptoms but address the root cause of the disease by targeting the repair and at most the regeneration of the damaged tissue. Historically, cells from adult tissue sources have been the most commonly tested in clinical trials encompassing almost all kinds of diseases. However, the recognition of their drawbacks, such as limited differentiation potential and poor scalability, has led the field to increasingly consider more immature cells, particularly pluripotent stem cells (PSCs) as attractive alternates. Indeed, the therapeutic interest of these cells is not so much their theoretically unlimited availability or scalability (as these properties can be shared by some adult cells such as mesenchymal stromal cells [MSCs]) but rather lies on the unique possibility to leverage their intrinsic pluripotentiality to drive them toward any cell type, provided they receive the appropriate lineage-specific cues and to control this differentiation process by way of “freezing” it at the desired stage (early progenitors or more mature cells)—all properties that adult cells lack. In this article, we will review the main PSC trials and discuss the safety challenges they may raise. “Tissue repair” for heart failure will be taken as a case study since it illustrates most of these challenges and allows discussion of some of the solutions based on the presumed mechanism of action of the transplanted cells. Chronologically, the first PSCs to enter the clinical arena have targeted traumatic spinal cord injury. The program was initiated by Geron Corporation, which launched a phase I trial of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells in October 2010 but stopped it 1 year later when it shifted focus toward cancer therapeutics. The technology assets were then acquired by Asterias Biotherapeutics, which subsequently initiated the SciStar trial in which 35 patients with subacute cervical spinal cord injury were transplanted with the same hESC-derived progenitor cells according to a dose-escalating regimen (up to 20 × 106 cells). In January, 2019, the company reported 12-month results in 25 patients showing the absence of safety issues and encouraging improvements in upper extremity motor function. The second organ that has been targeted by hESC-differentiated derivatives is the eye, which features several attractive characteristics for stem cell therapy, including easy access, presumed immune privilege, requirements for low dosages, and high compartmentalization reducing the risk of systemic spread. Age-related macular degeneration (AMD) has been so far the primary indication. The first trial (Schwartz et al., 2015Schwartz S.D. Regillo C.D. Lam B.L. Eliott D. Rosenfeld P.J. Gregori N.Z. Hubschman J.-P. Davis J.L. Heilwell G. Spirn M. et al.Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies.Lancet. 2015; 385: 509-516Abstract Full Text Full Text PDF PubMed Scopus (532) Google Scholar) enrolled 18 patients (9 with AMD and 9 with Stargardt’s macular dystrophy) who were followed up for 22 months after subretinal transplantation of increasing doses of hESC-derived retinal pigment epithelial (RPE) cells (from 50,000 to 150,000). The only adverse events were related to surgery and immunosuppression, but improvements in visual acuity were observed in more than half of the treated eyes. A similar trend was reported in a smaller series of 4 patients (Song et al., 2015Song W.K. Park K.-M. Kim H.-J. Lee J.H. Choi J. Chong S.Y. Shim S.H. Del Priore L.V. Lanza R. Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients.Stem Cell Reports. 2015; 4: 860-872Abstract Full Text Full Text PDF PubMed Google Scholar), while another trial including 12 patients with advanced Stargardt’s disease failed to show a significant benefit on retinal function at 12 months, possibly because of the severity of established retinal degeneration (Mehat et al., 2018Mehat M.S. Sundaram V. Ripamonti C. Robson A.G. Smith A.J. Borooah S. Robinson M. Rosenthal A.N. Innes W. Weleber R.G. et al.Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration.Ophthalmology. 2018; 125: 1765-1775Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar). In contrast, a visual acuity gain was recently reported in two small-sized trials in which injections of cell suspensions were replaced by transplantation of a bioengineered construct whereby hESC-derived RPE were seeded onto a polyester (da Cruz et al., 2018da Cruz L. Fynes K. Georgiadis O. Kerby J. Luo Y.H. Ahmado A. Vernon A. Daniels J.T. Nommiste B. Hasan S.M. et al.Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration.Nat. Biotechnol. 2018; 36: 328-337Crossref PubMed Scopus (69) Google Scholar) or a parylene scaffold (Kashani et al., 2018Kashani A.H. Lebkowski J.S. Rahhal F.M. Avery R.L. Salehi-Had H. Dang W. Lin C.-M. Mitra D. Zhu D. Thomas B.B. et al.A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration.Sci. Transl. Med. 2018; 10 (Published online April 4, 2018)https://doi.org/10.1126/scitranslmed.aao4097Crossref PubMed Scopus (33) Google Scholar) mimicking a Bruch’s membrane. This delivery modality may have contributed to a more successful outcome by preventing a de-differentiation of RPE cells that may occur when they are dissociated and requires their challenging re-differentiation in vivo to form a functional monolayer (Carr et al., 2013Carr A.-J.F. Smart M.J.K. Ramsden C.M. Powner M.B. da Cruz L. Coffey P.J. Development of human embryonic stem cell therapies for age-related macular degeneration.Trends Neurosci. 2013; 36: 385-395Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar). As shown in Table S1, several other trials are currently enrolling patients, and their outcomes will allow us to better define the place of PSC-derived RPE in comparison with other cell types (Higuchi et al., 2017Higuchi A. Kumar S.S. Benelli G. Alarfaj A.A. Munusamy M.A. Umezawa A. Murugan K. Stem Cell Therapies for Reversing Vision Loss.Trends Biotechnol. 2017; 35: 1102-1117Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). The brain of patients with Parkinson’s disease is another potential indication for PSC derivatives because of their ability to be differentiated into midbrain dopaminergic neurons and the capacity of these cells, following intracerebral transplantation, to rescue motor behavior deficits in animal models of the disease (Sonntag et al., 2018Sonntag K.-C. Song B. Lee N. Jung J.H. Cha Y. Leblanc P. Neff C. Kong S.W. Carter B.S. Schweitzer J. Kim K.S. Pluripotent stem cell-based therapy for Parkinson’s disease: Current status and future prospects.Prog. Neurobiol. 2018; 168: 1-20Crossref PubMed Scopus (8) Google Scholar), including those involving nonhuman primates (Kikuchi et al., 2017Kikuchi T. Morizane A. Doi D. Magotani H. Onoe H. Hayashi T. Mizuma H. Takara S. Takahashi R. Inoue H. et al.Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model.Nature. 2017; 548: 592-596Crossref PubMed Scopus (0) Google Scholar). Whether these encouraging preclinical data can translate into similar improvements in patients is being currently tested in a Chinese trial (Table S1). Likewise, a deeper understanding of the signaling pathways driving the endodermal layer toward the generation of pancreatic islet cells has allowed the in vitro recapitulation of this stepwise process and paved the way for a diabetes treatment based on the use of beta-like cells differentiated from human PSCs (hPSCs) (Sneddon et al., 2018Sneddon J.B. Tang Q. Stock P. Bluestone J.A. Roy S. Desai T. Hebrok M. Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges.Cell Stem Cell. 2018; 22: 810-823Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). To mitigate their rejection and reduce (or at most eliminate) the need for immunosuppressive drugs, these cells have usually been encapsulated in alginate-based microparticles with the premise that the capsule membrane would protect the cells from the host’s immune system while allowing an influx of oxygen and nutrients and an appropriate release of insulin. A major limitation of this encapsulation strategy has been a foreign-body reaction and a subsequent fibrosis around the capsules limiting the long-term function of the graft. Efforts have thus been made to optimize the formulation of the alginate particles (Strand et al., 2017Strand B.L. Coron A.E. Skjak-Braek G. Current and Future Perspectives on Alginate Encapsulated Pancreatic Islet.Stem Cells Transl. Med. 2017; 6: 1053-1058Crossref PubMed Scopus (25) Google Scholar). In August 2014, the company ViaCyte launched the STEP ONE∗ trial (NCT02239354) for evaluating the safety and efficacy of ViaCyte’s PEC-Encap in type I diabetes. The product consists of pancreatic progenitor cells delivered in a subcutaneously implanted and retrievable immune-encapsulation device (Encaptra). In June, 2018, the company reported encouraging 2-year outcomes in 19 patients with no safety issues, no evidence for allo-immunization to donor cells in the absence of immunosuppression, and differentiation into insulin-producing beta cells and glucagon-producing alpha cells in several explants. The delivery system is now undergoing changes to enhance long-term cell engraftment, and the company hopes to resume the STEP ONE trial enrolment in 2019. While islet survival may be compromised by their destruction by endogenous immune cells, hypovascularization of the graft can further contribute to hamper their sustained therapeutic benefit. Efforts have thus been made to enhance microvascularization of the encased islets, which has translated clinically into two different approaches. In 2017, ViaCyte has started the 55-patient PEC-Direct trial (NCT03163511) in which the company’s ESC-derived pancreatic progenitors are delivered in a device designed to allow their direct vascularization (Table S1). A potential drawback of the open design of this device is that the patients need to be immunosuppressed. Alternatively, Sernova has developed a cell pouch that is implanted subcutaneously to enable the creation of a vascularized environment intended to nurture islets, which are then transplanted in the pouch 2–12 weeks later. A trial testing this concept (NCT01652911) has included 3 patients and is now terminated, but no outcome data have been reported yet. A subsequent phase I/II nonrandomized, unblinded, single-arm study was announced in May 2018. A last challenge is that, in vivo, beta cells do not exist isolated but clustered within three-dimensional niches also harboring nonendocrine vascular cells and extracellular matrix components, hence the possible interest of an in vitro co-aggregation of allogeneic (human) islet cells with MSCs, which has resulted in their engraftment in the omentum of immunocompetent mice and allowed glycemic control without immunosuppression (Westenfelder et al., 2017Westenfelder C. Gooch A. Hu Z. Ahlstrom J. Zhang P. Durable Control of Autoimmune Diabetes in Mice Achieved by Intraperitoneal Transplantation of “Neo-Islets,” Three-Dimensional Aggregates of Allogeneic Islet and “Mesenchymal Stem Cells”.Stem Cells Transl. Med. 2017; 6: 1631-1643Crossref PubMed Scopus (7) Google Scholar). In the case of heart failure, the first cells that have been implanted clinically in the myocardium have been noncardiac, i.e., skeletal myoblasts and bone-marrow-derived cells. Although they have globally failed to yield clinically meaningful improvements in patient outcomes (Menasché et al., 2018Menasché P. Vanneaux V. Hagège A. Bel A. Cholley B. Parouchev A. Cacciapuoti I. Al-Daccak R. Benhamouda N. Blons H. et al.Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction.J. Am. Coll. Cardiol. 2018; 71: 429-438Crossref PubMed Scopus (40) Google Scholar, Fisher et al., 2016Fisher S.A. Doree C. Mathur A. Taggart D.P. Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure.Cochrane Database Syst. Rev. 2016; 12: CD007888PubMed Google Scholar), they have fuelled a burgeoning multifaceted area of research. Currently, however, only CD34-positive (Vrtovec, 2018Vrtovec B. Cell Therapy for Nonischemic Cardiomyopathy: Current Status and Future Perspectives.Circ. Res. 2018; 122: 28-30Crossref PubMed Scopus (0) Google Scholar) and, to a greater extent, mesenchymal cells (MSCs) continue to generate a clinical interest. Whereas the angiogeneic properties of the former may qualify them for treating refractory angina (Henry et al., 2018Henry T.D. Losordo D.W. Traverse J.H. Schatz R.A. Jolicoeur E.M. Schaer G.L. Clare R. Chiswell K. White C.J. Fortuin F.D. et al.Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials.Eur. Heart J. 2018; 39: 2208-2216Crossref PubMed Scopus (21) Google Scholar), the latter are attractive in the context of heart failure because of their alleged angiogeneic, anti-inflammatory, and immunomodulatory properties. Indeed, by March 2019, entering the keywords “chronic heart failure” and “mesenchymal stromal cells” in the ClinicalTrials.gov website retrieved 24 trials, among which the event-driven DREAM-HF study generates a strong interest because of its large sample size (566 patients randomized to receive allogeneic MSCs or placebo). The last patient has recently been dosed, and trial outcomes might become available within the next 12 months. Despite the interest in strategies employing noncardiac cell therapy, an important output of research in the area of cardiac repair has been the recognition that better outcomes might be achieved with cells phenotypically close to those of the target organ. This gave rise to the second generation of clinical trials entailing the use of cardiac-committed cells. Expectedly, the first ones to enter the clinical arena have used adult sources, but, so far, they have equally failed to result in substantial clinical benefits. The CHART-1 trial, which randomized 315 patients, of whom 157 received transendocardial injections of autologous MSCs engineered in vitro to express cardiac transcription factors, missed its primary endpoint (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction at 39 weeks) (Bartunek et al., 2017Bartunek J. Terzic A. Davison B.A. Filippatos G.S. Radovanovic S. Beleslin B. Merkely B. Musialek P. Wojakowski W. Andreka P. et al.CHART ProgramCardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial.Eur. Heart J. 2017; 38: 648-660PubMed Google Scholar) even though a post hoc data analysis provided evidence for reverse remodeling in a subset of patients (Teerlink et al., 2017Teerlink J.R. Metra M. Filippatos G.S. Davison B.A. Bartunek J. Terzic A. Gersh B.J. Povsic T.J. Henry T.D. Alexandre B. et al.CHART InvestigatorsBenefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study.Eur. J. Heart Fail. 2017; 19: 1520-1529Crossref PubMed Scopus (12) Google Scholar). The ALLSTAR trial tested cells derived from cardiospheres, which are composed of several cell types, predominantly MSCs, harvested from the right ventricle by an endomyocardial biopsy (Smith et al., 2007Smith R.R. Barile L. Cho H.C. Leppo M.K. Hare J.M. Messina E. Giacomello A. Abraham M.R. Marbán E. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens.Circulation. 2007; 115: 896-908Crossref PubMed Scopus (831) Google Scholar); this trial was prematurely terminated in April 2017 for futility. A third small-sized study (SCIPIO) tested c-kit+ “cardiac stem cells” grown from a right atrial biopsy taken during a coronary artery bypass grafting operation and injected (at the very low dose of 1 million) into the coronary arteries an average of 113 days later in 16 patients (while 7 served as controls). The authors’ initial enthusiastic claims (Bolli et al., 2011Bolli R. Chugh A.R. D’Amario D. Loughran J.H. Stoddard M.F. Ikram S. Beache G.M. Wagner S.G. Leri A. Hosoda T. et al.Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.Lancet. 2011; 378: 1847-1857Abstract Full Text PDF PubMed Scopus (1011) Google Scholar, Chugh et al., 2012Chugh A.R. Beache G.M. Loughran J.H. Mewton N. Elmore J.B. Kajstura J. Pappas P. Tatooles A. Stoddard M.F. Lima J.A.C. et al.Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance.Circulation. 2012; 126: S54-S64Crossref PubMed Scopus (0) Google Scholar) are seriously questioned by the recent retraction by Harvard Medical School of 31 papers, which had overall rationalized the use of these cells (Science, 2018Science A.A. News at a glance.Science. 2018; 362: 268-270Crossref PubMed Scopus (1) Google Scholar), now largely recognized as unable to give rise to cardiomyocytes (van Berlo et al., 2014van Berlo J.H. Kanisicak O. Maillet M. Vagnozzi R.J. Karch J. Lin S.-C.J. Middleton R.C. Marbán E. Molkentin J.D. c-kit+ cells minimally contribute cardiomyocytes to the heart.Nature. 2014; 509: 337-341Crossref PubMed Scopus (405) Google Scholar). In parallel, other groups, including ours, have taken a different approach consisting of starting from PSCs, in practice hESCs, and coaxing them to generate cardiac cells closer to the native ones, either at a progenitor state (Bellamy et al., 2015Bellamy V. Vanneaux V. Bel A. Nemetalla H. Emmanuelle Boitard S. Farouz Y. Joanne P. Perier M.-C. Robidel E. Mandet C. et al.Long-term functional benefits of human embryonic stem cell-derived cardiac progenitors embedded into a fibrin scaffold.J. Heart Lung Transplant. 2015; 34: 1198-1207Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar) or more fully differentiated into cardiomyocytes (Liu et al., 2018Liu Y.-W. Chen B. Yang X. Fugate J.A. Kalucki F.A. Futakuchi-Tsuchida A. Couture L. Vogel K.W. Astley C.A. Baldessari A. et al.Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates.Nat. Biotechnol. 2018; 36: 597-605Crossref PubMed Scopus (51) Google Scholar). Thus, in our clinical study (ESCORT, NCT02057900), we have used early-committed Isl-1+ progenitors embedded in a fibrin gel, which was then delivered onto the epicardium of the infarct area during a coronary artery bypass grafting in 6 patients with severe left ventricular dysfunction (Menasché et al., 2018Menasché P. Vanneaux V. Hagège A. Bel A. Cholley B. Parouchev A. Cacciapuoti I. Al-Daccak R. Benhamouda N. Blons H. et al.Transplantation of Human Embryonic Stem Cell-Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction.J. Am. Coll. Cardiol. 2018; 71: 429-438Crossref PubMed Scopus (40) Google Scholar). Aside from demonstrating that generation of such a composite construct was doable under Good Manufacturing Practice (GMP) standards, our trial successfully met its primary safety endpoint in that, with a maximal follow-up of 4 years and 5 months in March 2019, none of the patients has presented complications that could be specifically ascribed to the cells (arrhythmias, tumor, clinically relevant allo-immunization). By virtue of its design, the trial cannot answer the question of efficacy and the improved systolic thickening of the cell-treated (and nonrevascularized) myocardial areas seen in some patients can, at most, be considered as an encouraging hint. Other trials using hESC-derived more differentiated cardiomyocytes are currently in preparation in the United States and Canada. While ESCs have been the first PSC to be tested clinically and continue to be evaluated across a wide range of diseases (summarized in Table S1), they are now followed by the use of induced pluripotent stem cells (iPSCs). The first trial, initiated in Japan, used iPSC-differentiated RPE derivatives for treating macular degeneration. The study, however, was stopped after one patient had been injected because of concerns about genetic changes in the cells prepared for the second one (Mandai et al., 2017Mandai M. Watanabe A. Kurimoto Y. Hirami Y. Morinaga C. Daimon T. Fujihara M. Akimaru H. Sakai N. Shibata Y. et al.Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration.N. Engl. J. Med. 2017; 376: 1038-1046Crossref PubMed Scopus (293) Google Scholar). This has led the investigators to redesign the protocol and switch to the use of allogeneic banked iPSCs, which have then successfully passed all quality controls. So far, one patient has been transplanted and there are 4 more to come. Another trial testing allogeneic iPSC-derived dopamine precursor cells in patients with Parkinson’s disease was started in October 2018, and six more patients are planned for inclusion (Cyranoski, 2018Cyranoski D. ‘Reprogrammed’ stem cells implanted into patient with Parkinson’s disease.Nature. 2018; (Published online November 14, 2018)https://doi.org/10.1038/d41586-018-07407-9Crossref Google Scholar), while two additional studies in spinal cord injury (Cyranoski, 2018Cyranoski D. ‘Reprogrammed’ stem cells implanted into patient with Parkinson’s disease.Nature. 2018; (Published online November 14, 2018)https://doi.org/10.1038/d41586-018-07407-9Crossref Google Scholar) and corneal diseases (Cyranoski, 2019Cyranoski D. Japan poised to allow ‘reprogrammed’ stem-cell therapy for damaged corneas.Nature Res. 2019; (Published online April 10, 2019)https://go.nature.com/2G2bT3AGoogle Scholar) have been approved (these three trials in Japan). Heart failure is also targeted by iPSC therapies and two trials are in preparation, one in Japan and the other in Germany, in which iPSC-derived cardiomyocytes will be transplanted in combination with a scaffold through a limited surgical approach. A third trial (HEAL-CHF), conducted in China, is already registered (NCT 03763136) and should include 5 patients with heart failure receiving intramyocardial injections of allogeneic iPSCs at the time of coronary artery bypass grafting. It is noteworthy that for practical and economic reasons, the initially claimed advantage of iPSCs over ESCs, i.e., the possibility of using them in an autologous fashion, has been abandoned in favor of allogeneic banked iPSCs. The balance between the advantages (consistency of the final cell product, streamlined logistics, and lower costs) and drawbacks (rejection) of this allogeneic strategy will be discussed in another section of this article. To summarize, taken together, all these cell therapy trials have primarily demonstrated the safety of the procedure (5 patients of the initial spinal cord injury trial have now reached 8 years of follow-up without reporting serious adverse events), while few of them have yet been designed and powered to really show efficacy. Although the interpretation of their results is further complicated by the diversity of patient disease, cell processing protocols, dosing, timing and route of delivery, duration of follow-up, and outcome measures, some encouraging hints are emerging, which makes credible that PSC-derived differentiated progenies or their secreted products (see below) can find a place within the armamentarium of therapies against a variety of life-threatening or functionally invalidating human diseases. Of note, the outcome metrics of current and upcoming PSC trials will have to be analyzed in light of those of the competing therapies, which are also extensively investigated for treating the same disorders such as gene therapy for ocular diseases (Ramlogan-Steel et al., 2018Ramlogan-Steel C.A. Murali A. Andrzejewski S. Dhungel B. Steel J.C. Layton C.J. Gene therapy and the adeno-associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations.Clin. Exp. Ophthalmol. 2018; 47: 521-536Crossref Scopus (5) Google Scholar), automated insulin delivery devices for diabetes (Latres et al., 2019Latres E. Finan D.A. Greenstein J.L. Kowalski A. Kieffer T.J. Navigating Two Roads to Glucose Normalization in Diabetes: Automated Insulin Delivery Devices and Cell Therapy.Cell Metab. 2019; 29: 545-563Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), or direct intracerebral administration of growth factors for Parkinson’s disease (Whone et al., 2019Whone A. Luz M. Boca M. Woolley M. Mooney L. Dharia S. Broadfoot J. Cronin D. Schroers C. Barua N.U. et al.Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease.Brain. 2019; 142: 512-525Crossref PubMed Scopus (18) Google Scholar). Cells are usually injected directly into the target organ, but this procedure can damage both the host tissue and the cells themselves as they incur a dramatic increase in flow velocity and shear stresses as they flow from the syringe to the small bore needle (Aguado et al., 2012Aguado B.A. Mulyasasmita W. Su J. Lampe K.J. Heilshorn S.C. Improving viability of stem cells during syringe needle flow through the design of hydrogel cell carriers.Tissue Eng. Part A. 2012; 18: 806-815Crossref PubMed Scopus (272) Google Scholar). In addition, unlike fluids, cells in suspension tend to sediment in a time-dependent manner, which may induce a density gradient leading to uneven cell dispersion (and thus variable cell dosing) when multiple injections are performed from the same syringe with the highest cell densities during the first injection (Potts et al., 2013Potts M.B. Silvestrini M.T. Lim D.A. Devices for cell transplantation into the central nervous system: Design considerations and emerging technologies.Surg. Neurol. Int. 2013; 4: S22-S30PubMed Google Scholar). Efforts are thus made to improve the accuracy of targeting while minimizing its invasiveness. Typical examples are the use of MRI to provide real-time imaging for stereotactic procedures and of a radially branched deployment device for intra-cerebral (Potts et al., 2013Potts M.B. Silvestrini M.T. Lim D.A. Devices for cell transplantation into the central nervous system: Design considerations and emerging technologies.Surg. Neurol. Int. 2013; 4: S22-S30PubMed Google Scholar) or the development of a device for delivering RPE without creating a hole in the retina (Orbit Biomedical). In the heart, the main routes for cell injections have usually been trans-epicardial, trans-endocardial, or intra-coronary. Even though the direct intra-myocardial approach seems the most effective (Hou et al., 2005Hou D. Youssef E.A.-S. Brinton T.J. Zhang P. Rogers P. Price E.T. Yeung A.C. Johnstone B.H. Yock P.G. March K.L. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: implications for current clinical trials.Circulation. 2005; 112: I150-I156PubMed Google Scholar), it is still fraught with a poor retention rate. This likely hinders a successful therapeutic outcome because, as supported by the experimental (Levit et al., 2013Levit R.D. Landázuri N. Phelps E.A. Brown M.E. García A.J. Davis M.E. Joseph G. Long R. Safley S.A. Suever J.D. et al.Cellular encapsulation enhances cardiac repair.J. A" @default.
• W2984490538 created "2019-11-22" @default.
• W2984490538 creator A5051472273 @default.
• W2984490538 creator A5063067802 @default.
• W2984490538 date "2019-11-01" @default.
• W2984490538 modified "2023-10-16" @default.
• W2984490538 title "Clinical Translation of Pluripotent Stem Cell Therapies: Challenges and Considerations" @default.
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