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A New Generation of MSC Applications
With scientific results dismally challenging to replicate properly across disciplines, scientists, technologists, or investors with intact survival instincts cannot be naïve. No matter how gruff it sounds, a healthy respect for due diligence and fiduciary responsibility demands that good people ask, “Where’s the beef!?” at any time. In Part I of this article, we first heard about “MSC 2.0,” 17 which is the second generation of mesenchymal stem/stromal cell (MSC) cellular technology. Like T cells, MSCs are a raw primary cellular source that irrigates multiple branches of downstream clinical applications that intermingle with other technologies. Although one potentially promising use of “v2.0” involves cell-cultured and/or cruelty-free meat (aka “clean meat”), 76 we aim to inform you here that MSC 2.0 now supports other—more near-term—ventures of direct benefit to human health.
MSC-EVs: Engineered Nanomedicines from (and for) the Body Electric
EVs (extracellular vesicles)—sometimes referred to as exosomes 77 —are abundantly secreted 78 into conditioned media by MSC 79 bioproduction systems. It’s been compellingly 80 demonstrated 81 that part or even most of the therapeutic effect 82 of MSCs could be due to EVs released into the “secretome.” 83 MSC-EVs’ naturally intrinsic benefit along with their engineerability turbocharged them into the pole position for an assortment of next-generation advanced therapies. 80, 84, 85, 86, 87, 88, 89, 90, 91, 92
Compared with derivatives of HEK-293 cells (the mainstay for gene therapy vector production and many vaccines), MSCs don’t have a transformed phenotype. Furthermore, EVs from MSCs may uniquely express biological activities of therapeutic value, such as via localized CD73/adenosine 93, 94 or miRNA 95 cargoes. Accordingly, mesenchymal stromal/stem cells (MSCs) have advanced to the leading edge of cellular bioproduction sources of extracellular vesicles for human clinical trials. 80, 96, 97 “Why bother why bother buying the cow when you can directly buy the milk?” expresses a widely-voiced apropos analogy. 98
In the case of monoclonal antibodies, heavily engineered CHO cells are the “cows” and their mAb products are the “milk” for an industry valued at over $200B in global sales. 99 Likewise, to secure MSC 2.0 as a domain for EV/exosome manufacturing, ongoing efforts are underway to generate rejuvenated and clonal MSCs from iPSCs, immortalized (yet non-transformed) MSC cell lines, improved gene transfer methods, and MSC-friendly upstream 100 and downstream 101 processes that can ultimately be scalable into bioreactor batch runs of over 1000 liters. 102 Of course, the biggest breakthroughs are yet to be realized, determined by new synthetic biologists and product developers who aim to derivatize these macromolecular particles with novel surface ligands and intraluminal cargoes. 88, 103, 104, 105
Two to Tango: Co-cultured Cell Partners for MSCs’ Dance with the Stars
In other applications of MSC 2.0, the MSCs are essential cellular components for a separate cell therapy. That is, they may “educate” co-cultured cells of a different origin to induce them into a more uniformly beneficial phenotype for re-implantation. In one example, 106 Dr. Ashish Patel of King’s College London combined standardized preparations of allogeneic, off-the-shelf MSCs with ex vivo autologous patient monocytes. This procedure converts monocytes from a pro-inflammatory, pre-phagocytic cell into a potent mix of anti-fibrotic, pro-angiogenic, and anti-inflammatory cells. Given instant availability of stockpiled, clinical grade cGMP MSC cell material, a recent Phase I trial against COVID-19 107 was rolled out at lightning speed via qualified biomaterials, regulatory approvals, and patients lined up within eight months.
Still more examples of MSC 2.0 might include co-administered MSCs along with a partner cell type, such as Foxp3+ Tregs, in future human trials. With Dr. Charles Cox’s team of the University of Texas Health Center, it was shown that the combination of Tregs and MSCs for treatment of a model traumatic brain injury (TBI) 7 was superior to either cell type administered alone. This and similar in vivo results for conditions such as GvHD, 108 recurrent spontaneous abortion, 109 retinal ischemic injury, 110 multiple sclerosis, 111 and many 112 other conditions suggest a possible synergy 113 between MOAs of immunosuppressive T cell subtypes and MSCs. 114 In parallel applications that have advanced into early human trials, initial observations show that co-infused MSCs may develop a pro-tolerogenic environment for organ transplants, 115 reducing the doses (and side effects) of immunosuppressive drugs and risk of acute rejection. In addition, MSCs are being explored to optimize regenerative therapy outcomes when co-administered with chondrocytes for treatment of focal cartilage defects, 116, 117 along with other indications. 118
Induced pluripotent stem cells (iPSCs) open the gates to an entire landscape of downstream therapeutic and drug screening cellular technologies. 119 Their derivative cell types can be used as targets for libraries of “druggable” combinatorial chemicals as well as genetically defined disease model systems or as a source of “rejuvenated” cellular raw materials for dosed human therapeutics in regenerative medicine or immune oncology. iPSCs via MSCs do not merely comprise a compelling starting material that is potentially fully traceable and regulatory-compliant for future cell types of clinical translation interest. 120 MSCs can also be engineered as “feeder cells” to assist in generation and propagation 121, 122 of new iPSC clones. The ease of mass MSC culture and its plug-and-play industrial supply chain of xeno-free, clinical grade materials could solve some of the issues challenges of variable quality and non-human features of mouse embryonic fibroblasts (MEFs).
Differentiation for Potentiation
While MSCs are often considered to serve immunosuppressive roles, Dr. Moutih Rafei and colleagues at Defence Therapeutics recently devised a means to polarize these cells 123 in the opposite direction towards potent antigen presentation. 23 With Accum™ technology, MSCs are coaxed to work as an “off-the-shelf Universal vaccine” that can synergize with immune checkpoint blocking mAbs. Functioning as programmable dendritic-like cells but without the onerous manufacturing pitfalls, these exhibited powerful anti-tumor efficacy in animal models and are en route to a Phase I trial in melanoma patients.
The capability for MSCs to exhibit unique cell fate plasticity beyond the prototypical “tri-lineage” (fat, bone, cartilage) is also relevant to neurology. Here are just two of many other examples. A readily available and abundant source of replacement neuron-like cells for treatment of Parkinson’s Disease, ALS, or other neurodegenerative conditions might be possible from MSCs that are induced to transdifferentiate into neurons. 124 Induced cholinergic-like neurons could also credibly model ex vivo simulations of diseases like familial Alzheimer’s, 125 of conceivable benefit to high throughput (HTS) compound library screening.
MSCs as Programmable Trojan Horses for Drug Delivery
Another theme of MSCs as anti-cancer weapons deploys them as “Trojan horses” for oncolytic viruses. That is, the MSCs may increase the amount of oncolytic virus that’s in proximity to the tumor, widening the window of efficacy in lieu of direct tumor injections. In 2019, Calidi Biotherapeutics completed a small, Phase I trial with ACAM2000, 126 a thymidine kinase positive vaccinia virus delivered by adipose MSCs into various solid and liquid tumors. Similarly, oncolytic adenovirus has been used by Dr. Manuel Ramírez and associates of the Hospital Universitario Niño Jesús to treat refractory or relapsed solid tumors in nine children and seven adults in a Phase I trial. 127 This approach is also being leveraged by trials for glioblastoma at MD Anderson Cancer Center (NCT03896568) and for ovarian carcinomas at the Mayo Clinic (NCT02068794).
MSC 2.0 drug delivery techs do not necessarily solely rely on “spicy,” tumor-melting viruses to selectively target and/or control a bioactive ingredient, of course. An especially fascinating such technology is hosted by Tel Aviv’s nanoGhost, 128 which removes the nuclei of MSCs and uses their membranes as small bags for a pipeline of targeted proteins, small molecules, or mRNA drugs. Cytonus (Carlsbad, CA) 129 has devised alternative methods for its MSC-derived drug delivery platform, which combines AI therapeutic engineering with its enucleated (yet otherwise intact) cell systems that promise spatiotemporal control over the precision release of biologic drugs.
MSCs Help Medical Innovations Flow into Vascular Engineering and Pro-Angiogenesis Applications
One of the “super-powers” of MSCs (including secretome and immune-modulation) relates to their apparent mundane “day job” as a pericyte or pericyte-like cell. 130 On injury to a vascular net, pericytes and their MSC kinfolk can help plug the leak and promote angiogenesis. As putative progenitor cells, they can also be coaxed to differentiate into vessel-lining endothelial cells 131 as well as contractile smooth muscle, 132 and they can favorably respond to hypoxic stimuli 133 and form nascent microvascular morphologies. 134 Initially, such features naturally inspired development of “MSC 1.0” therapeutic approaches that have been aimed at ischemia related indications such as heart failure 135, 136 and acute myocardial infarction. 137 An MSC 2.0 modality that might plausibly bridge the bumpy “efficacy gap” observed between many Phase II and Phase III trials is genetic modification of MSCs with pro-survival and pro-regenerative factors such as SDF-1, 138 EPO, 139 VEGF, 140 or synergistic multi-gene combinations. 141
Exciting developments are underway not merely for classic cell therapies, but rather MSCs that are printed or layered into artificial tissues that could be constructed to meet profound unmet medical needs. MSCs have been shown to perform more robustly than primary smooth muscle cells in some ex vivo experimental contexts to devise tissue engineered blood vessels (TEBVs). 142 One format of scaffolded TEBV is the TEVG, or tissue engineered vascular graft, which can also be seeded ex vivo with MSCs that gradually remodel the device into a functional blood vessel when re-implanted in vivo. 143 Having already demonstrated dramatic in vivo data, such bioengineered constructs could potentially resolve a shortage facing thousands of patients who await high quality, living blood vessel grafts for repair of aortic aneurisms. 144, 145, 146 MSCs not only help restore or manufacture blood vessels; they cooperate as important cell ingredients to vascularize tissue engineered bone, highlighting a possible material for reconstructive surgeries following serious injuries. 22, 147
Mitochondria from MSCs for Advanced Therapy Power-Ups
It almost sounds like science fiction, but 2 billion years of evolution and almost 20 years of investigation has validated the idea that MSCs donate mitochondria to ailing neighbor cells 148, 149 in disease lesions or zones of oxidative stress. Can this natural physiologic mechanism be mimicked to augment novel human medicines? Answer: yes, and the field is advancing perhaps farther than you might think. 150 At least seven human trials report mitochondrial transplantation as the MOA, and four of these appear to source these organelles directly from MSCs. Several commercial ventures use MSCs to further this goal, including Mitrix Bio, Minovia, celllvie, PEAN Biotechnology, LUCA Science, Mitosense, and Taiwan Mitochondrion Applied Technology Co. Although extensive future work will be needed (perhaps with the help of MSC 2.0 cellular platforms), transplanted mitochondria may have already saved the lives of neonatal infants in cardiac arrest, as reported in the New York Times.
Cell and Gene Therapy “Building Blocks” for MSC “Engine Blocks”
“By 2005 or so, it will become clear that the Internet’s impact on the economy has been no greater than the fax machine’s.”
–Nobel Prize Winning Economist, Paul Krugman, 1998
By the time Professor Krugman provocatively threw shade on the “dial-up” Internet of 1998, its core protocol for data exchange via the 1960s-era “ARPANET” predecessor was already 15 years old. Krugman would have been keenly aware that this emerging tech platform had already taken decades to develop. And he was directionally correct that the Web’s inflection point for mass adoption could be challenging to predict when it was then hamstrung by a lack of interested users and proportional connection nodes. “Most people have nothing to say to each other,” he quipped. However, what he may have missed was the hard work with infrastructure development and value creation modes that was already churning behind the scenes.
The long latency to load a single page would soon be ancient history with arrival of DSL, fiber optic, and 3G connections. And the iPhone? Less than a decade away. Due to subtle process innovations underlying each year’s new hardware and software, the internet first gradually and then swiftly became democratized—ubiquitous on every continent to serve a large majority of the world’s population. Similarly, many challenges that once plagued early MSC clinical products (with their outdated, regulatory-cemented bioprocesses) a decade ago are now solved due to a robust, industrialized supply chain with parallel reductions in the cost and time per billion cells. The bioproduction path to rapid MSC doses for patients in need has never been easier, with these undergoing a digital-like democratization toward worldwide access.
Young travelers riding the family “wheels” like to notoriously ask “Are we there yet?!” 17 However, to prematurely declare “yes” for an emerging technology might be “putting the CAR-T before the horse,” as some had cautioned the immune oncology field in the early 2010s, fretting about a replay of the Dendreon saga wherein a promising (yet highly complex) cell-drug faced manufacturing and scalability headaches. For the Internet of 1998, the answer was also “no,” as the standards and infrastructure (e.g., “roads”) were not yet firmly established. Likewise, MSCs are not quite “there yet,” but for different reasons than what was faced by T cell or Silicon Valley pioneers. In contrast to the ‘98 internet, however, the material and process infrastructure for MSC therapies are largely already built. That is, the obstacles to MSCs are now mostly conceptual and regulatory in nature.
One possible accelerant for MSCs effective navigation of the road ahead (as well as CAR-Ts and all cell and gene therapies) has been called technology platform “building blocks.” This concept 151 was recently explored in a working session co-sponsored by the Alliance for Regenerative Medicine (ARM) and the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL). The modular nature of synthetic gene construction combined with the toolkit of diverse cultured cell types and their phenotypes lends itself to rapid, bespoke solutions to both common and extremely rare human disease conditions. On the other hand, these novel therapies and cures are necessarily complex; with each minor modification to each component or process, an entire new drug process must begin again with a new IND and years of costly development.
A “building block” represents a reusable platform technology designation that could “improve time and resource efficiency of CGT development and regulatory review” that could be quickly transplanted across diverse clinical programs. A specific example might be a validated genome editing molecular toolset of CRISPR reagents and best practices. For MSCs, this building block could conceivably involve a master cell bank (MCB) and/or its paired bioreactor expansion medium and optimized process. The novel “MSC 2.0” therapy might thus involve a combination of two blocks: the standardized CRISPR system and the accompanying MSC bioprocess platform. We would not need to reinvent the wheel with each platform over and over. Given the plight of patients with only months left to live, a new IND could ideally be launched in weeks, not years.
Recent often-cited projections do not predict a plateauing of “Peak MSC” demand until the 2040s. 17 Why? Accessibility of clinical grade MSC’s with highly optimized bioprocessing conditions is now leading to more testing and experimentation than ever before. Despite recent speedbumps with MSC 1.0 in late-Phase clinical trials, mesenchymal stem/stromal cells (MSCs) are undergoing a significant evolution known as MSC 2.0, akin to the transformative journey observed in CAR-T cell therapy. Uses in clinical and/or consumer products that will supersede MSC 1.0 are likely to include tissue engineered products, muti-cell combinations, cosmeceuticals, products secreted or extracted from MSCs, MSCs derived from iPSCs, and others.
Looking at the current innovation space, it appears that hundreds of pre-commercial entities, startups, and existing biotechs already plan to incorporate MSC 2.0 into trials over the coming years. Expected progression of the MSC operating system, coupled with the right recipes for clinical success, could further accelerate waves of new therapies. This shift of focus towards “forward engineering” cell therapies emphasizes the role of genetic design and advanced bioprocessing in unlocking the full potential of MSCs. MSC 2.0’s exploration of novel applications, including extracellular vesicles, and innovative drug delivery systems will converge these concepts and position MSC 2.0 as a guide for the future development of these cells, paving the way for precision medicine and integrated regenerative therapies.
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References:
- Pittenger, M. F.; Mackay, A. M.; Beck, S. C.; Jaiswal, R. K.; Douglas, R.; Mosca, J. D.; Moorman, M. A.; Simonetti, D. W.; Craig, S.; Marshak, D. R., Multilineage potential of adult human mesenchymal stem cells. Science 1999, 284 (5411), 143-7. 10.1126/science.284.5411.143
- Chamberlain, J. R.; Schwarze, U.; Wang, P. R.; Hirata, R. K.; Hankenson, K. D.; Pace, J. M.; Underwood, R. A.; Song, K. M.; Sussman, M.; Byers, P. H.; Russell, D. W., Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science 2004, 303 (5661), 1198-201. 10.1126/science.1088757
- Grigoryan, B.; Paulsen, S. J.; Corbett, D. C.; Sazer, D. W.; Fortin, C. L.; Zaita, A. J.; Greenfield, P. T.; Calafat, N. J.; Gounley, J. P.; Ta, A. H.; Johansson, F.; Randles, A.; Rosenkrantz, J. E.; Louis-Rosenberg, J. D.; Galie, P. A.; Stevens, K. R.; Miller, J. S., Multivascular networks and functional intravascular topologies within biocompatible hydrogels. Science 2019, 364 (6439), 458-464. 10.1126/science.aav9750
- Kurita, M.; Araoka, T.; Hishida, T.; O’Keefe, D. D.; Takahashi, Y.; Sakamoto, A.; Sakurai, M.; Suzuki, K.; Wu, J.; Yamamoto, M.; Hernandez-Benitez, R.; Ocampo, A.; Reddy, P.; Shokhirev, M. N.; Magistretti, P.; Nunez Delicado, E.; Eto, H.; Harii, K.; Izpisua Belmonte, J. C., In vivo reprogramming of wound-resident cells generates skin epithelial tissue. Nature 2018, 561 (7722), 243-247. 10.1038/s41586-018-0477-4
- Mansouri, M.; Hussherr, M. D.; Strittmatter, T.; Buchmann, P.; Xue, S.; Camenisch, G.; Fussenegger, M., Smart-watch-programmed green-light-operated percutaneous control of therapeutic transgenes. Nat Commun 2021, 12 (1), 3388. 10.1038/s41467-021-23572-4
- Kojima, R.; Scheller, L.; Fussenegger, M., Nonimmune cells equipped with T-cell-receptor-like signaling for cancer cell ablation. Nat Chem Biol 2018, 14 (1), 42-49. 10.1038/nchembio.2498
- Caplan, H. W.; Prabhakara, K. S.; Toledano Furman, N. E.; Zorofchian, S.; Kumar, A.; Martin, C.; Xue, H.; Olson, S. D.; Cox, C. S., Jr., Combination therapy with Treg and mesenchymal stromal cells enhances potency and attenuation of inflammation after traumatic brain injury compared to monotherapy. Stem Cells 2021, 39 (3), 358-370. 10.1002/stem.3320
- Foresti, D.; Kroll, K. T.; Amissah, R.; Sillani, F.; Homan, K. A.; Poulikakos, D.; Lewis, J. A., Acoustophoretic printing. Sci Adv 2018, 4 (8), eaat1659. 10.1126/sciadv.aat1659
- Nieland, L.; Mahjoum, S.; Grandell, E.; Breyne, K.; Breakefield, X. O., Engineered EVs designed to target diseases of the CNS. J Control Release 2023, 356, 493-506. 10.1016/j.jconrel.2023.03.009
- Kojima, R.; Bojar, D.; Rizzi, G.; Hamri, G. C.; El-Baba, M. D.; Saxena, P.; Auslander, S.; Tan, K. R.; Fussenegger, M., Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson’s disease treatment. Nat Commun 2018, 9 (1), 1305. 10.1038/s41467-018-03733-8
- Armstrong, A., Athersys inches closer to bankruptcy as stroke cell therapy fails interim analysis. https://www.fiercebiotech.com/biotech/athersys-inches-closer-bankruptcy-stroke-cell-therapy-fails-interim-analysis.
- Manalac, T., Mesoblast Sees Path Forward for Twice-Rejected Cell Therapy After FDA Meeting. https://www.biospace.com/article/mesoblast-sees-path-forward-for-twice-rejected-cell-therapy-after-fda-meeting/.
- Lewis, R., FDA Returns Disappointing News for ALS Stem Cell Therapy. https://dnascience.plos.org/2023/10/19/fda-returns-disappointing-news-for-als-stem-cell-therapy/.
- Takeda Announces Topline Results of Phase 3 ADMIRE-CD II Trial of Alofisel® (darvadstrocel) in Complex Crohn’s Perianal Fistulas. https://www.businesswire.com/news/home/20231017954354/en.
- Gartner Hype Cycle – Interpreting technology hype. https://www.gartner.com/en/research/methodologies/gartner-hype-cycle.
- Lembong, J.; Carson, J.; Rowley, J., The Stabilization of hMSCs as a Technology. https://www.roosterbio.com/blog/white-paper-the-stabilization-of-hmscs-as-a-technology/.
- Olsen, T. R.; Ng, K. S.; Lock, L. T.; Ahsan, T.; Rowley, J. A., Peak MSC-Are We There Yet? Front Med (Lausanne) 2018, 5, 178. 10.3389/fmed.2018.00178
- Schoonraad, S. A.; Jaimes, A. A.; Singh, A. J. X.; Croland, K. J.; Bryant, S. J., Osteogenic effects of covalently tethered rhBMP-2 and rhBMP-9 in an MMP-sensitive PEG hydrogel nanocomposite. Acta Biomater 2023, 170, 53-67. 10.1016/j.actbio.2023.08.045
- Chiang, C. L.; Ma, Y.; Hou, Y. C.; Pan, J.; Chen, S. Y.; Chien, M. H.; Zhang, Z. X.; Hsu, W. H.; Wang, X.; Zhang, J.; Li, H.; Sun, L.; Fallen, S.; Lee, I.; Chen, X. Y.; Chu, Y. S.; Zhang, C.; Cheng, T. S.; Jiang, W.; Kim, B. Y. S.; Reategui, E.; Lee, R.; Yuan, Y.; Liu, H. C.; Wang, K.; Hsiao, M.; Huang, C. F.; Shan, Y. S.; Lee, A. S.; James Lee, L., Dual targeted extracellular vesicles regulate oncogenic genes in advanced pancreatic cancer. Nat Commun 2023, 14 (1), 6692. 10.1038/s41467-023-42402-3
- Chan, T.; Prabhu, A.; Elayadi, A.; Williams, L.; Dailey, V.; Elliot, K.; Snipas, T.; Carson, J.; Lewis, J.; Schauer, S., Abstract C234: Regulated immunomodulators expression using the RheoSwitch Therapeutic System® platform in human mesenchymal stem cells. Molecular Cancer Therapeutics 2013, 12 (11_Supplement), C234-C234.
- Rovira Gonzalez, Y. I.; Lynch, P. J.; Thompson, E. E.; Stultz, B. G.; Hursh, D. A., In vitro cytokine licensing induces persistent permissive chromatin at the Indoleamine 2,3-dioxygenase promoter. Cytotherapy 2016, 18 (9), 1114-28. 10.1016/j.jcyt.2016.05.017
- Schott, N. G.; Vu, H.; Stegemann, J. P., Multimodular vascularized bone construct comprised of vasculogenic and osteogenic microtissues. Biotechnol Bioeng 2022, 119 (11), 3284-3296. 10.1002/bit.28201
- Salame, N.; Bikorimana, J. P.; El-Hachem, N.; Saad, W.; Kurdi, M.; Zhao, J.; Eliopoulos, N.; Shammaa, R.; Rafei, M., UM171A-induced ROS promote antigen cross-presentation of immunogenic peptides by bone marrow-derived mesenchymal stromal cells. Stem Cell Res Ther 2022, 13 (1), 16. 10.1186/s13287-021-02693-z
- Gundersen, R. A.; Chu, T.; Abolfathi, K.; Dogan, S. G.; Blair, P. E.; Nago, N.; Hamblin, M.; Brooke, G. N.; Zwacka, R. M.; Hoshiar, A. K.; Mohr, A., Generation of magnetic biohybrid microrobots based on MSC.sTRAIL for targeted stem cell delivery and treatment of cancer. Cancer Nanotechnol 2023, 14, 54. 10.1186/s12645-023-00203-9
- Tenchov, R.; Sasso, J. M.; Wang, X.; Liaw, W. S.; Chen, C. A.; Zhou, Q. A., Exosomes horizontal line Nature’s Lipid Nanoparticles, a Rising Star in Drug Delivery and Diagnostics. ACS Nano 2022, 16 (11), 17802-17846. 10.1021/acsnano.2c08774
- King, B. Appreciating Arnold Caplan’s Contributions to MSCs & Regenerative Medicine. https://www.roosterbio.com/blog/appreciating-arnold-caplans-contributions-to-mscs-regenerative-medicine/.
- Caplan, A. I., Mesenchymal stem cells. J Orthop Res 1991, 9 (5), 641-50. 10.1002/jor.1100090504
- Patel, A.; Candiello, J., Rapid translation of a cellular therapeutic from research to clinic. Cell and Gene Therapy Insights 2022, 08 (03), 445-445. 10.18609/cgti.2022.012
- An, S.; Anwar, K.; Ashraf, M.; Lee, H.; Jung, R.; Koganti, R.; Ghassemi, M.; Djalilian, A. R., Wound-Healing Effects of Mesenchymal Stromal Cell Secretome in the Cornea and the Role of Exosomes. Pharmaceutics 2023, 15 (5). 10.3390/pharmaceutics15051486
- Lee, R. H.; Boregowda, S. V.; Shigemoto-Kuroda, T.; Bae, E.; Haga, C. L.; Abbery, C. A.; Bayless, K. J.; Haskell, A.; Gregory, C. A.; Ortiz, L. A.; Phinney, D. G., TWIST1 and TSG6 are coordinately regulated and function as potency biomarkers in human MSCs. Sci Adv 2023, 9 (45), eadi2387. 10.1126/sciadv.adi2387
- Carson, J., Analytics: Time to Scratch the “30-Year Itch” from MSCs’ Questions. https://www.roosterbio.com/blog/analytics-time-to-scratch-the-30-year-itch-from-mscs-questions/.
- Wakitani, S.; Mera, H.; Nakamura, N.; Gobbi, A., Review of Caplan (1991) on cell-based therapeutic technology using Mesenchymal Stem Cells. J ISAKOS 2023. 10.1016/j.jisako.2023.08.010
- Caplan, A. I.; Sorrell, J. M., The MSC curtain that stops the immune system. Immunol Lett 2015, 168 (2), 136-9. 10.1016/j.imlet.2015.06.005
- Caplan, A. I., MSCs: The Sentinel and Safe-Guards of Injury. J Cell Physiol 2016, 231 (7), 1413-6. 10.1002/jcp.25255
- Caplan, A. I., Mesenchymal Stem Cells: Time to Change the Name! Stem Cells Transl Med 2017, 6 (6), 1445-1451. 10.1002/sctm.17-0051
- Mukkala, A. N.; Jerkic, M.; Khan, Z.; Szaszi, K.; Kapus, A.; Rotstein, O., Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control. Int J Mol Sci 2023, 24 (21). 10.3390/ijms242115788
- Carson, J., MSCs & Precision Medicine: Mining a “Galaxy” of Answers for the “Ultimate” Questions. https://www.roosterbio.com/blog/mscs-and-precision-medicine-mining-a-galaxy-of-answers-for-the-ultimate-questions/.
- Rosenberg, S. A.; Restifo, N. P.; Yang, J. C.; Morgan, R. A.; Dudley, M. E., Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008, 8 (4), 299-308. 10.1038/nrc2355
- Rosenberg, S. A.; Packard, B. S.; Aebersold, P. M.; Solomon, D.; Topalian, S. L.; Toy, S. T.; Simon, P.; Lotze, M. T.; Yang, J. C.; Seipp, C. A.; et al., Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 1988, 319 (25), 1676-80. 10.1056/NEJM198812223192527
- FDA Approves First Cellular Therapy to Treat Patients with Unresectable or Metastatic Melanoma. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma.
- Cohen, C. J.; Gartner, J. J.; Horovitz-Fried, M.; Shamalov, K.; Trebska-McGowan, K.; Bliskovsky, V. V.; Parkhurst, M. R.; Ankri, C.; Prickett, T. D.; Crystal, J. S.; Li, Y. F.; El-Gamil, M.; Rosenberg, S. A.; Robbins, P. F., Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J Clin Invest 2015, 125 (10), 3981-91. 10.1172/JCI82416
- Eshhar, Z.; Gross, G.; Waks, T., ENDOWING CELLS WITH ANTIBODY SPECIFICITY USING CHIMERIC T CELL RECEPTOR. IL 86278 A, 1988/05/04, 2003.
- Kuwana, Y.; Kurosawa, Y.; Itou, S., NOVEL CHIMERA POLYPEPTIDE. JP S6463394 A, 1987/09/04, 1989.
- Kuwana, Y.; Asakura, Y.; Utsunomiya, N.; Nakanishi, M.; Arata, Y.; Itoh, S.; Nagase, F.; Kurosawa, Y., Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem Biophys Res Commun 1987, 149 (3), 960-8. 10.1016/0006-291x(87)90502-x
- Gross, G.; Waks, T.; Eshhar, Z., Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A 1989, 86 (24), 10024-8. 10.1073/pnas.86.24.10024
- Moritz, D.; Wels, W.; Mattern, J.; Groner, B., Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2-expressing tumor cells. Proc Natl Acad Sci U S A 1994, 91 (10), 4318-22. 10.1073/pnas.91.10.4318
- Krause, A.; Guo, H. F.; Latouche, J. B.; Tan, C.; Cheung, N. K.; Sadelain, M., Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med 1998, 188 (4), 619-26. 10.1084/jem.188.4.619
- Finney, H. M.; Lawson, A. D.; Bebbington, C. R.; Weir, A. N., Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol 1998, 161 (6), 2791-7. https://www.ncbi.nlm.nih.gov/pubmed/9743337
- Ying, Z.; He, T.; Wang, X.; Zheng, W.; Lin, N.; Tu, M.; Xie, Y.; Ping, L.; Zhang, C.; Liu, W.; Deng, L.; Qi, F.; Ding, Y.; Lu, X. A.; Song, Y.; Zhu, J., Parallel Comparison of 4-1BB or CD28 Co-stimulated CD19-Targeted CAR-T Cells for B Cell Non-Hodgkin’s Lymphoma. Mol Ther Oncolytics 2019, 15, 60-68. 10.1016/j.omto.2019.08.002
- Morgan, R. A.; Yang, J. C.; Kitano, M.; Dudley, M. E.; Laurencot, C. M.; Rosenberg, S. A., Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010, 18 (4), 843-51. 10.1038/mt.2010.24
- Cameron, B. J.; Gerry, A. B.; Dukes, J.; Harper, J. V.; Kannan, V.; Bianchi, F. C.; Grand, F.; Brewer, J. E.; Gupta, M.; Plesa, G.; Bossi, G.; Vuidepot, A.; Powlesland, A. S.; Legg, A.; Adams, K. J.; Bennett, A. D.; Pumphrey, N. J.; Williams, D. D.; Binder-Scholl, G.; Kulikovskaya, I.; Levine, B. L.; Riley, J. L.; Varela-Rohena, A.; Stadtmauer, E. A.; Rapoport, A. P.; Linette, G. P.; June, C. H.; Hassan, N. J.; Kalos, M.; Jakobsen, B. K., Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med 2013, 5 (197), 197ra103. 10.1126/scitranslmed.3006034
- Brudno, J. N.; Kochenderfer, J. N., Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 2016, 127 (26), 3321-30. 10.1182/blood-2016-04-703751
- Porter, D. L.; Levine, B. L.; Kalos, M.; Bagg, A.; June, C. H., Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011, 365 (8), 725-33. 10.1056/NEJMoa1103849
- Brentjens, R. J.; Davila, M. L.; Riviere, I.; Park, J.; Wang, X.; Cowell, L. G.; Bartido, S.; Stefanski, J.; Taylor, C.; Olszewska, M.; Borquez-Ojeda, O.; Qu, J.; Wasielewska, T.; He, Q.; Bernal, Y.; Rijo, I. V.; Hedvat, C.; Kobos, R.; Curran, K.; Steinherz, P.; Jurcic, J.; Rosenblat, T.; Maslak, P.; Frattini, M.; Sadelain, M., CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013, 5 (177), 177ra38. 10.1126/scitranslmed.3005930
- Chen, Y. J.; Abila, B.; Mostafa Kamel, Y., CAR-T: What Is Next? Cancers (Basel) 2023, 15 (3). 10.3390/cancers15030663
- Bio, F. A. B. G.; Baker, D.; Church, G.; Collins, J.; Endy, D.; Jacobson, J.; Keasling, J.; Modrich, P.; Smolke, C.; Weiss, R., Engineering life: building a fab for biology. Sci Am 2006, 294 (6), 44-51. 10.1038/scientificamerican0606-44
- Kojima, R.; Aubel, D.; Fussenegger, M., Building sophisticated sensors of extracellular cues that enable mammalian cells to work as “doctors” in the body. Cell Mol Life Sci 2020, 77 (18), 3567-3581. 10.1007/s00018-020-03486-y
- Braendstrup, P.; Levine, B. L.; Ruella, M., The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19. Cytotherapy 2020, 22 (2), 57-69. 10.1016/j.jcyt.2019.12.004
- Caplan, A. I., All MSCs are pericytes? Cell Stem Cell 2008, 3 (3), 229-30. 10.1016/j.stem.2008.08.008
- Caplan, A. I.; Correa, D., The MSC: an injury drugstore. Cell Stem Cell 2011, 9 (1), 11-5. 10.1016/j.stem.2011.06.008
- Dimarino, A. M.; Caplan, A. I.; Bonfield, T. L., Mesenchymal stem cells in tissue repair. Front Immunol 2013, 4, 201. 10.3389/fimmu.2013.00201
- Gomez-Ferrer, M.; Villanueva-Badenas, E.; Sanchez-Sanchez, R.; Sanchez-Lopez, C. M.; Baquero, M. C.; Sepulveda, P.; Dorronsoro, A., HIF-1alpha and Pro-Inflammatory Signaling Improves the Immunomodulatory Activity of MSC-Derived Extracellular Vesicles. Int J Mol Sci 2021, 22 (7). 10.3390/ijms22073416
- Podesta, M. A.; Remuzzi, G.; Casiraghi, F., Mesenchymal Stromal Cells for Transplant Tolerance. Front Immunol 2019, 10, 1287. 10.3389/fimmu.2019.01287
- Boberg, E.; von Bahr, L.; Afram, G.; Lindstrom, C.; Ljungman, P.; Heldring, N.; Petzelbauer, P.; Garming Legert, K.; Kadri, N.; Le Blanc, K., Treatment of chronic GvHD with mesenchymal stromal cells induces durable responses: A phase II study. Stem Cells Transl Med 2020, 9 (10), 1190-1202. 10.1002/sctm.20-0099
- Lembong, J.; Kirian, R.; Takacs, J. D.; Olsen, T. R.; Lock, L. T.; Rowley, J. A.; Ahsan, T., Bioreactor Parameters for Microcarrier-Based Human MSC Expansion under Xeno-Free Conditions in a Vertical-Wheel System. Bioengineering (Basel) 2020, 7 (3). 10.3390/bioengineering7030073
- Jossen, V.; van den Bos, C.; Eibl, R.; Eibl, D., Manufacturing human mesenchymal stem cells at clinical scale: process and regulatory challenges. Appl Microbiol Biotechnol 2018, 102 (9), 3981-3994. 10.1007/s00253-018-8912-x
- Kirian, R.; Wang, D.; Takacs, J.; Tsai, A.; Cruz, K.; Rosello, F.; Cox, K.; Hashimura, Y.; Lembong, J.; Rowley, J., Scaling a xeno-free fed-batch microcarrier suspension bioreactor system from development to production scale for manufacturing XF hMSCs. Cytotherapy 2019, 21 (5), S71-S72.
- Lembong, J.; Rowley, J., Building Effective Multi-Year Process Development Programs II: Evolution of Technology Platform Decisions Based on Lot Size. https://www.roosterbio.com/blog/building-effective-multi-year-process-development-programs-ii-evolution-of-technology-platform-decisions-based-on-lot-size/.
- Lembong, J.; Rowley, J., Building Effective Multi-Year Process Development Programs I: Estimating hMSC Lot Size Ranges for Clinical Manufacturing Through Commercial Demand. https://www.roosterbio.com/blog/building-effective-multi-year-process-development-programs-i/.
- Adlerz, K., Critical Quality Attributes (CQAs): Know Their Importance & Limitations in Product & Process Development. https://www.roosterbio.com/blog/critical-quality-attributes-cqas-know-their-importance-limitations-in-product-process-development/.
- Lembong, J. Identify & Define Your Cell Therapy’s Biomanufacturing Approach for Critical Process Parameters (CPPs). https://www.roosterbio.com/blog/identify-define-your-cell-therapys-biomanufacturing-approach-for-critical-process-parameters-cpps/.
- Campbell, A.; Brieva, T.; Raviv, L.; Rowley, J.; Niss, K.; Brandwein, H.; Oh, S.; Karnieli, O., Concise Review: Process Development Considerations for Cell Therapy. Stem Cells Transl Med 2015, 4 (10), 1155-63. 10.5966/sctm.2014-0294
- Phase III Clinical Trials – Ever Wonder Why Some Products Unexpectedly Fail? https://ispe.org/pharmaceutical-engineering/ispeak/phase-iii-clinical-trials-ever-wonder-why-some-products-unexpectedly-fail.
- Robb, K. P.; Fitzgerald, J. C.; Barry, F.; Viswanathan, S., Mesenchymal stromal cell therapy: progress in manufacturing and assessments of potency. Cytotherapy 2019, 21 (3), 289-306. 10.1016/j.jcyt.2018.10.014
- Rowley, J.; Carson, J.; Adherent Cell Manufacturing’s Call to Action. https://tinyurl.com/yrjdsp4u
- Lee, M.; Park, S.; Choi, B.; Choi, W.; Lee, H.; Lee, J. M.; Lee, S. T.; Yoo, K. H.; Han, D.; Bang, G.; Hwang, H.; Koh, W. G.; Lee, S.; Hong, J., Cultured meat with enriched organoleptic properties by regulating cell differentiation. Nat Commun 2024, 15 (1), 77. 10.1038/s41467-023-44359-9
- Kalluri, R.; LeBleu, V. S., The biology, function, and biomedical applications of exosomes. Science 2020, 367 (6478). 10.1126/science.aau6977
- Yeo, R. W.; Lai, R. C.; Zhang, B.; Tan, S. S.; Yin, Y.; Teh, B. J.; Lim, S. K., Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev 2013, 65 (3), 336-41. 10.1016/j.addr.2012.07.001
- Xunian, Z.; Kalluri, R., Biology and therapeutic potential of mesenchymal stem cell-derived exosomes. Cancer Sci 2020, 111 (9), 3100-3110. 10.1111/cas.14563
- Toh, W. S.; Yarani, R.; El Andaloussi, S.; Cho, B. S.; Choi, C.; Corteling, R.; De Fougerolles, A.; Gimona, M.; Herz, J.; Khoury, M.; Robbins, P. D.; Williams, D.; Weiss, D. J.; Rohde, E.; Giebel, B.; Lim, S. K., A report on the International Society for Cell & Gene Therapy 2022 Scientific Signature Series, “Therapeutic advances with native and engineered human extracellular vesicles”. Cytotherapy 2023, 25 (8), 810-814. 10.1016/j.jcyt.2023.02.009
- Kordelas, L.; Rebmann, V.; Ludwig, A. K.; Radtke, S.; Ruesing, J.; Doeppner, T. R.; Epple, M.; Horn, P. A.; Beelen, D. W.; Giebel, B., MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 2014, 28 (4), 970-3. 10.1038/leu.2014.41
- Giebel, B.; Kordelas, L.; Borger, V., Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig 2017, 4, 84. 10.21037/sci.2017.09.06
- Mansouri, N.; Willis, G. R.; Fernandez-Gonzalez, A.; Reis, M.; Nassiri, S.; Mitsialis, S. A.; Kourembanas, S., Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes. JCI Insight 2019, 4 (21). 10.1172/jci.insight.128060
- Kim, S. H.; Bianco, N.; Menon, R.; Lechman, E. R.; Shufesky, W. J.; Morelli, A. E.; Robbins, P. D., Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol Ther 2006, 13 (2), 289-300. 10.1016/j.ymthe.2005.09.015
- Zeelenberg, I. S.; Ostrowski, M.; Krumeich, S.; Bobrie, A.; Jancic, C.; Boissonnas, A.; Delcayre, A.; Le Pecq, J. B.; Combadiere, B.; Amigorena, S.; Thery, C., Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses. Cancer Res 2008, 68 (4), 1228-35. 10.1158/0008-5472.CAN-07-3163
- Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M. J., Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011, 29 (4), 341-5. 10.1038/nbt.1807
- Wahlgren, J.; Statello, L.; Skogberg, G.; Telemo, E.; Valadi, H., Delivery of Small Interfering RNAs to Cells via Exosomes. Methods Mol Biol 2016, 1364, 105-25. 10.1007/978-1-4939-3112-5_10
- Stranford, D. M.; Leonard, J. N., Delivery of Biomolecules via Extracellular Vesicles: A Budding Therapeutic Strategy. Adv Genet 2017, 98, 155-175. 10.1016/bs.adgen.2017.08.002
- Izco, M.; Blesa, J.; Schleef, M.; Schmeer, M.; Porcari, R.; Al-Shawi, R.; Ellmerich, S.; de Toro, M.; Gardiner, C.; Seow, Y.; Reinares-Sebastian, A.; Forcen, R.; Simons, J. P.; Bellotti, V.; Cooper, J. M.; Alvarez-Erviti, L., Systemic Exosomal Delivery of shRNA Minicircles Prevents Parkinsonian Pathology. Mol Ther 2019, 27 (12), 2111-2122. 10.1016/j.ymthe.2019.08.010
- Kooijmans, S. A. A.; de Jong, O. G.; Schiffelers, R. M., Exploring interactions between extracellular vesicles and cells for innovative drug delivery system design. Adv Drug Deliv Rev 2021, 173, 252-278. 10.1016/j.addr.2021.03.017
- Gupta, D.; Wiklander, O. P. B.; Gorgens, A.; Conceicao, M.; Corso, G.; Liang, X.; Seow, Y.; Balusu, S.; Feldin, U.; Bostancioglu, B.; Jawad, R.; Mamand, D. R.; Lee, Y. X. F.; Hean, J.; Mager, I.; Roberts, T. C.; Gustafsson, M.; Mohammad, D. K.; Sork, H.; Backlund, A.; Lundin, P.; de Fougerolles, A.; Smith, C. I. E.; Wood, M. J. A.; Vandenbroucke, R. E.; Nordin, J. Z.; El-Andaloussi, S., Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles. Nat Biomed Eng 2021, 5 (9), 1084-1098. 10.1038/s41551-021-00792-z
- Mitrut, R. E.; Stranford, D. M.; Chan, J. M.; Bailey, M. D.; Luo, M.; Meade, T. J.; Wang, M.; Leonard, J. N., HaloTag display enables quantitative single-particle characterization and functionalization of engineered extracellular vesicles. bioRxiv 2023. 10.1101/2023.09.25.559433
- Tan, K.; Zhu, H.; Zhang, J.; Ouyang, W.; Tang, J.; Zhang, Y.; Qiu, L.; Liu, X.; Ding, Z.; Deng, X., CD73 Expression on Mesenchymal Stem Cells Dictates the Reparative Properties via Its Anti-Inflammatory Activity. Stem Cells Int 2019, 2019, 8717694. 10.1155/2019/8717694
- Cramer, M., CD73: A Team Player Caught in the “AKT” of Wound Healing & Cell Survival via MSC Exosomes? https://www.roosterbio.com/blog/cd73-a-team-player-caught-in-the-akt-of-wound-healing-cell-survival-via-msc-exosomes/.
- Arminian, A.; Carson, J.; Lenzini, Stephen, miRNA, miRNA in the QIAzol®, Where’s the Fingerprint Among Them All? https://www.roosterbio.com/blog/mirna-mirna-in-the-qiazol-wheres-the-fingerprint-among-them-all/.
- Lenzini, S., Big Effects in Small Packages: What Are Extracellular Vesicles, Exosomes, & Microvesicles & Why Are They En Route to the Clinic? https://www.roosterbio.com/blog/big-effects-in-small-packages-what-are-extracellular-vesicles-exosomes-microvesicles-why-are-they-en-route-to-the-clinic/.
- Yarani, R.; Lim, S. K.; Giebel, B., Mesenchymal stromal cells extracellular vesicles; unlocking the potential. Cytotherapy 2023, 25 (8), 808-809. 10.1016/j.jcyt.2023.05.008
- Sharma, D.; Zhao, F., Updates on clinical trials evaluating the regenerative potential of allogenic mesenchymal stem cells in COVID-19. NPJ Regen Med 2021, 6 (1), 37. 10.1038/s41536-021-00147-x
- Biopharma Dealmakers, Moving up with the monoclonals. Nat. Rev. Drug Discov 2018, 17, 855. 10.1038/d43747-020-00765-2
- Lenzini, S., Extracellular Vesicle/Exosome Upstream Process Development: Maximizing Productivity to Accelerate Clinical Adoption. https://www.roosterbio.com/blog/extracellular-vesicle-exosome-upstream-process-development-maximizing-productivity-to-accelerate-clinical-adoption/.
- Jung, J. L., Stephen Extracellular Vesicle/Exosome Downstream Process Development Part I: Leveraging Filtration Technologies for Scalable EV Preparation. https://www.roosterbio.com/blog/extracellular-vesicle-exosome-downstream-process-development-part-i-leveraging-filtration-technologies-for-scalable-ev-preparation/.
- From Elephant Ears to Ambr® Waves: A New Path Toward Scale & Abundance for Biomanufactured hMSCs & Their Exosomes. https://www.roosterbio.com/blog/from-elephant-ears-to-ambr-waves-a-new-path-toward-scale-abundance-for-biomanufactured-hmscs-their-exosomes/.
- Osteikoetxea, X.; Silva, A.; Lazaro-Ibanez, E.; Salmond, N.; Shatnyeva, O.; Stein, J.; Schick, J.; Wren, S.; Lindgren, J.; Firth, M.; Madsen, A.; Mayr, L. M.; Overman, R.; Davies, R.; Dekker, N., Engineered Cas9 extracellular vesicles as a novel gene editing tool. J Extracell Vesicles 2022, 11 (5), e12225. 10.1002/jev2.12225
- Picon, M. A.; Wang, L.; Da Fonseca Ferreira, A.; Dong, C.; Marzouka, G. R., Extracellular Vesicles as Delivery Systems in Disease Therapy. Int J Mol Sci 2023, 24 (24). 10.3390/ijms242417134
- Teng, F.; Fussenegger, M., Shedding Light on Extracellular Vesicle Biogenesis and Bioengineering. Adv Sci (Weinh) 2020, 8 (1), 2003505. 10.1002/advs.202003505
- Patel, A., Accelerating the Development of a Novel Cell Therapy for COVID-19–Associated Lung Fibrosis. https://www.pharmasalmanac.com/articles/accelerating-the-development-of-a-novel-cell-therapy-for-covid-19-associated-lung-fibrosis.
- Guy’s-and-St-Thomas’-NHS-Foundation-Trust NCT04805086 – The MONACO Cell Therapy Study: Monocytes as an Anti-fibrotic Treatment After COVID-19 (MONACO). https://clinicaltrials.gov/study/NCT04805086.
- Lim, J. Y.; Park, M. J.; Im, K. I.; Kim, N.; Jeon, E. J.; Kim, E. J.; Cho, M. L.; Cho, S. G., Combination cell therapy using mesenchymal stem cells and regulatory T-cells provides a synergistic immunomodulatory effect associated with reciprocal regulation of TH1/TH2 and th17/treg cells in a murine acute graft-versus-host disease model. Cell Transplant 2014, 23 (6), 703-14. 10.3727/096368913X664577
- Zhang, D.; Lin, Y.; Li, Y.; Zhao, D.; Du, M., Mesenchymal stem cells enhance Treg immunosuppressive function at the fetal-maternal interface. J Reprod Immunol 2021, 148, 103366. 10.1016/j.jri.2021.103366
- Agrawal, M.; Rasiah, P. K.; Bajwa, A.; Rajasingh, J.; Gangaraju, R., Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury. Cells 2021, 10 (11). 10.3390/cells10113006
- Bai, L.; Lennon, D. P.; Eaton, V.; Maier, K.; Caplan, A. I.; Miller, S. D.; Miller, R. H., Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009, 57 (11), 1192-203. 10.1002/glia.20841
- Piekarska, K.; Urban-Wojciuk, Z.; Kurkowiak, M.; Pelikant-Malecka, I.; Schumacher, A.; Sakowska, J.; Spodnik, J. H.; Arcimowicz, L.; Zielinska, H.; Tymoniuk, B.; Renkielska, A.; Siebert, J.; Slominska, E.; Trzonkowski, P.; Hupp, T.; Marek-Trzonkowska, N. M., Mesenchymal stem cells transfer mitochondria to allogeneic Tregs in an HLA-dependent manner improving their immunosuppressive activity. Nat Commun 2022, 13 (1), 856. 10.1038/s41467-022-28338-0
- Court, A. C.; Le-Gatt, A.; Luz-Crawford, P.; Parra, E.; Aliaga-Tobar, V.; Batiz, L. F.; Contreras, R. A.; Ortuzar, M. I.; Kurte, M.; Elizondo-Vega, R.; Maracaja-Coutinho, V.; Pino-Lagos, K.; Figueroa, F. E.; Khoury, M., Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep 2020, 21 (2), e48052. 10.15252/embr.201948052
- Luz-Crawford, P.; Kurte, M.; Bravo-Alegria, J.; Contreras, R.; Nova-Lamperti, E.; Tejedor, G.; Noel, D.; Jorgensen, C.; Figueroa, F.; Djouad, F.; Carrion, F., Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther 2013, 4 (3), 65. 10.1186/scrt216
- Deo, D.; Marchioni, M.; Rao, P., Mesenchymal Stem/Stromal Cells in Organ Transplantation. Pharmaceutics 2022, 14 (4). 10.3390/pharmaceutics14040791
- Saris, D. NCT05553132 – A Study of Recycled CartiLage Auto/Allo Implantation to Treat and Repair Focal Hip Cartilage Defects. https://clinicaltrials.gov/study/NCT05553132.
- Korpershoek, J. V.; Vonk, L. A.; Kester, E. C.; Creemers, L. B.; de Windt, T. S.; Kip, M. M. A.; Saris, D. B. F.; Custers, R. J. H., Efficacy of one-stage cartilage repair using allogeneic mesenchymal stromal cells and autologous chondron transplantation (IMPACT) compared to nonsurgical treatment for focal articular cartilage lesions of the knee: study protocol for a crossover randomized controlled trial. Trials 2020, 21 (1), 842. 10.1186/s13063-020-04771-8
- Le, H.; Xu, W.; Zhuang, X.; Chang, F.; Wang, Y.; Ding, J., Mesenchymal stem cells for cartilage regeneration. J Tissue Eng 2020, 11, 2041731420943839. 10.1177/2041731420943839
- Robinton, D. A.; Daley, G. Q., The promise of induced pluripotent stem cells in research and therapy. Nature 2012, 481 (7381), 295-305. 10.1038/nature10761
- Mohamed, A.; Chow, T.; Whiteley, J.; Fantin, A.; Sorra, K.; Hicks, R.; Rogers, I. M., Umbilical Cord Tissue as a Source of Young Cells for the Derivation of Induced Pluripotent Stem Cells Using Non-Integrating Episomal Vectors and Feeder-Free Conditions. Cells 2020, 10 (1). 10.3390/cells10010049
- Zou, C.; Chou, B. K.; Dowey, S. N.; Tsang, K.; Huang, X.; Liu, C. F.; Smith, C.; Yen, J.; Mali, P.; Zhang, Y. A.; Cheng, L.; Ye, Z., Efficient derivation and genetic modifications of human pluripotent stem cells on engineered human feeder cell lines. Stem Cells Dev 2012, 21 (12), 2298-311. 10.1089/scd.2011.0688
- Zou, Q.; Wu, M.; Zhong, L.; Fan, Z.; Zhang, B.; Chen, Q.; Ma, F., Development of a Xeno-Free Feeder-Layer System from Human Umbilical Cord Mesenchymal Stem Cells for Prolonged Expansion of Human Induced Pluripotent Stem Cells in Culture. PLoS One 2016, 11 (2), e0149023. 10.1371/journal.pone.0149023
- Hildreth, C. Defence Therapeutics Reports Reprogrammed MSC Vaccine Cures 80% of Animals with Lymphoma Cancer. https://bioinformant.com/defence-therapeutics-msc-vaccine/.
- Trzaska, K. A.; Rameshwar, P., Dopaminergic neuronal differentiation protocol for human mesenchymal stem cells. Methods Mol Biol 2011, 698, 295-303. 10.1007/978-1-60761-999-4_22
- Soto-Mercado, V.; Mendivil-Perez, M.; Velez-Pardo, C.; Lopera, F.; Jimenez-Del-Rio, M., Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal sAPPbeta fragments accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ dysregulation: Therapeutic implications. PLoS One 2020, 15 (5), e0221669. 10.1371/journal.pone.0221669
- Minev, B. R.; Lander, E.; Feller, J. F.; Berman, M.; Greenwood, B. M.; Minev, I.; Santidrian, A. F.; Nguyen, D.; Draganov, D.; Killinc, M. O.; Vyalkova, A.; Kesari, S.; McClay, E.; Carabulea, G.; Marincola, F. M.; Butterfield, L. H.; Szalay, A. A., First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells. J Transl Med 2019, 17 (1), 271. 10.1186/s12967-019-2011-3
- Ruano, D.; Lopez-Martin, J. A.; Moreno, L.; Lassaletta, A.; Bautista, F.; Andion, M.; Hernandez, C.; Gonzalez-Murillo, A.; Melen, G.; Alemany, R.; Madero, L.; Garcia-Castro, J.; Ramirez, M., First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors. Mol Ther 2020, 28 (4), 1033-1042. 10.1016/j.ymthe.2020.01.019
- Oieni, J.; Levy, L.; Letko Khait, N.; Yosef, L.; Schoen, B.; Fliman, M.; Shalom-Luxenburg, H.; Malkah Dayan, N.; D’Atri, D.; Cohen Anavy, N.; Machluf, M., Nano-Ghosts: Biomimetic membranal vesicles, technology and characterization. Methods 2020, 177, 126-134. 10.1016/j.ymeth.2019.11.013
- Wang, H.; Alarcon, C. N.; Liu, B.; Watson, F.; Searles, S.; Lee, C. K.; Keys, J.; Pi, W.; Allen, D.; Lammerding, J.; Bui, J. D.; Klemke, R. L., Genetically engineered and enucleated human mesenchymal stromal cells for the targeted delivery of therapeutics to diseased tissue. Nat Biomed Eng 2022, 6 (7), 882-897. 10.1038/s41551-021-00815-9
- Crisan, M.; Yap, S.; Casteilla, L.; Chen, C. W.; Corselli, M.; Park, T. S.; Andriolo, G.; Sun, B.; Zheng, B.; Zhang, L.; Norotte, C.; Teng, P. N.; Traas, J.; Schugar, R.; Deasy, B. M.; Badylak, S.; Buhring, H. J.; Giacobino, J. P.; Lazzari, L.; Huard, J.; Peault, B., A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008, 3 (3), 301-13. 10.1016/j.stem.2008.07.003
- Szoke, K.; Beckstrom, K. J.; Brinchmann, J. E., Human adipose tissue as a source of cells with angiogenic potential. Cell Transplant 2012, 21 (1), 235-50. 10.3727/096368911X580518
- Tian, H.; Bharadwaj, S.; Liu, Y.; Ma, H.; Ma, P. X.; Atala, A.; Zhang, Y., Myogenic differentiation of human bone marrow mesenchymal stem cells on a 3D nano fibrous scaffold for bladder tissue engineering. Biomaterials 2010, 31 (5), 870-7. 10.1016/j.biomaterials.2009.10.001
- Liu, L.; Gao, J.; Yuan, Y.; Chang, Q.; Liao, Y.; Lu, F., Hypoxia preconditioned human adipose derived mesenchymal stem cells enhance angiogenic potential via secretion of increased VEGF and bFGF. Cell Biol Int 2013, 37 (6), 551-60. 10.1002/cbin.10097
- Valarmathi, M. T.; Yost, M. J.; Goodwin, R. L.; Potts, J. D., A three-dimensional tubular scaffold that modulates the osteogenic and vasculogenic differentiation of rat bone marrow stromal cells. Tissue Eng Part A 2008, 14 (4), 491-504. 10.1089/tea.2007.0235
- Bolli, R.; Mitrani, R. D.; Hare, J. M.; Pepine, C. J.; Perin, E. C.; Willerson, J. T.; Traverse, J. H.; Henry, T. D.; Yang, P. C.; Murphy, M. P.; March, K. L.; Schulman, I. H.; Ikram, S.; Lee, D. P.; O’Brien, C.; Lima, J. A.; Ostovaneh, M. R.; Ambale-Venkatesh, B.; Lewis, G.; Khan, A.; Bacallao, K.; Valasaki, K.; Longsomboon, B.; Gee, A. P.; Richman, S.; Taylor, D. A.; Lai, D.; Sayre, S. L.; Bettencourt, J.; Vojvodic, R. W.; Cohen, M. L.; Simpson, L.; Aguilar, D.; Loghin, C.; Moye, L.; Ebert, R. F.; Davis, B. R.; Simari, R. D.; Cardiovascular Cell Therapy Research, N., A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. Eur J Heart Fail 2021, 23 (4), 661-674. 10.1002/ejhf.2178
- Bartolucci, J.; Verdugo, F. J.; Gonzalez, P. L.; Larrea, R. E.; Abarzua, E.; Goset, C.; Rojo, P.; Palma, I.; Lamich, R.; Pedreros, P. A.; Valdivia, G.; Lopez, V. M.; Nazzal, C.; Alcayaga-Miranda, F.; Cuenca, J.; Brobeck, M. J.; Patel, A. N.; Figueroa, F. E.; Khoury, M., Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]). Circ Res 2017, 121 (10), 1192-1204. 10.1161/CIRCRESAHA.117.310712
- White, I. A.; Sanina, C.; Balkan, W.; Hare, J. M., Mesenchymal Stem Cells in Cardiology. Methods Mol Biol 2016, 1416, 55-87. 10.1007/978-1-4939-3584-0_4
- Zhang, M.; Mal, N.; Kiedrowski, M.; Chacko, M.; Askari, A. T.; Popovic, Z. B.; Koc, O. N.; Penn, M. S., SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction. FASEB J 2007, 21 (12), 3197-207. 10.1096/fj.06-6558com
- Tsiftsoglou, A. S., Erythropoietin (EPO) as a Key Regulator of Erythropoiesis, Bone Remodeling and Endothelial Transdifferentiation of Multipotent Mesenchymal Stem Cells (MSCs): Implications in Regenerative Medicine. Cells 2021, 10 (8). 10.3390/cells10082140
- Yu, Q.; Fang, W.; Zhu, N.; Zheng, X.; Na, R.; Liu, B.; Meng, L.; Li, Z.; Li, Q.; Li, X., Beneficial effects of intramyocardial mesenchymal stem cells and VEGF165 plasmid injection in rats with furazolidone induced dilated cardiomyopathy. J Cell Mol Med 2015, 19 (8), 1868-76. 10.1111/jcmm.12558
- Jaruga-Killeen, E.; Bull, D. A.; Lotun, K.; Henry, T. D.; Egnaczyk, G.; Reed, T. D.; Patel, A. N., Safety of First in Human Triple-Gene Therapy Candidate for Heart Failure Patients. Circulation 2019, 140 (Suppl_1), A16296-A16296.
- Strobel, H. A.; Hookway, T. A.; Piola, M.; Fiore, G. B.; Soncini, M.; Alsberg, E.; Rolle, M. W., Assembly of Tissue-Engineered Blood Vessels with Spatially Controlled Heterogeneities. Tissue Eng Part A 2018, 24 (19-20), 1492-1503. 10.1089/ten.TEA.2017.0492
- Roh, J. D.; Sawh-Martinez, R.; Brennan, M. P.; Jay, S. M.; Devine, L.; Rao, D. A.; Yi, T.; Mirensky, T. L.; Nalbandian, A.; Udelsman, B.; Hibino, N.; Shinoka, T.; Saltzman, W. M.; Snyder, E.; Kyriakides, T. R.; Pober, J. S.; Breuer, C. K., Tissue-engineered vascular grafts transform into mature blood vessels via an inflammation-mediated process of vascular remodeling. Proc Natl Acad Sci U S A 2010, 107 (10), 4669-74. 10.1073/pnas.0911465107
- Haskett, D. G.; Saleh, K. S.; Lorentz, K. L.; Josowitz, A. D.; Luketich, S. K.; Weinbaum, J. S.; Kokai, L. E.; D’Amore, A.; Marra, K. G.; Rubin, J. P.; Wagner, W. R.; Vorp, D. A., An exploratory study on the preparation and evaluation of a “same-day” adipose stem cell-based tissue-engineered vascular graft. J Thorac Cardiovasc Surg 2018, 156 (5), 1814-1822 e3. 10.1016/j.jtcvs.2018.05.120
- MSC 2.0 Applications Stem the Progression of Vascular Conditions & Chronic Wounds: A Webinar Featuring Professor David Vorp & Students, https://www.roosterbio.com/blog/msc-2-0-applications-stem-the-progression-of-vascular-conditions-chronic-wounds-a-webinar-featuring-professor-david-vorp-students/.
- Gueldner, P. H.; Marini, A. X.; Li, B.; Darvish, C. J.; Chung, T. K.; Weinbaum, J. S.; Curci, J. A.; Vorp, D. A., Mechanical and matrix effects of short and long-duration exposure to beta-aminopropionitrile in elastase-induced model abdominal aortic aneurysm in mice. JVS Vasc Sci 2023, 4, 100098. 10.1016/j.jvssci.2023.100098
- Ude, C. C.; Miskon, A.; Idrus, R. B. H.; Abu Bakar, M. B., Application of stem cells in tissue engineering for defense medicine. Mil Med Res 2018, 5 (1), 7. 10.1186/s40779-018-0154-9
- Spees, J. L.; Olson, S. D.; Whitney, M. J.; Prockop, D. J., Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A 2006, 103 (5), 1283-8. 10.1073/pnas.0510511103
- Gomzikova, M. O.; James, V.; Rizvanov, A. A., Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies. Front Cell Dev Biol 2021, 9, 653322. 10.3389/fcell.2021.653322
- Mitochondria Transplantation Therapy – It’s Farther Along Than You Think. https://www.roosterbio.com/blog/mitochondria-transplantation-therapy-its-farther-along-than-you-think/.
- Alliance for Regenerative Medicine, FDA Scientific Exchange: Unlocking the Potential of Building Blocks to Expedite CGT Development and Review. https://alliancerm.org/arm-event/arm-fda-scientific-exchange-meeting-on-platform-technologies/.
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