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Stem cells

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Differential CXCR4 expression on hematopoietic progenitor cells versus stem cells directs homing and engraftment
Sydney Felker, … , Dylan Siniard, Punam Malik
Sydney Felker, … , Dylan Siniard, Punam Malik
Published May 9, 2022
Citation Information: JCI Insight. 2022;7(9):e151847. https://doi.org/10.1172/jci.insight.151847.
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Differential CXCR4 expression on hematopoietic progenitor cells versus stem cells directs homing and engraftment

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Abstract

Gene therapy involves a substantial loss of hematopoietic stem and progenitor cells (HSPC) during processing and homing. Intra-BM (i.b.m.) transplantation can reduce homing losses, but prior studies have not yielded promising results. We studied the mechanisms involved in homing and engraftment of i.b.m. transplanted and i.v. transplanted genetically modified (GM) human HSPC. We found that i.b.m. HSPC transplantation improved engraftment of hematopoietic progenitor cells (HPC) but not of long-term repopulating hematopoietic stem cells (HSC). Mechanistically, HPC expressed higher functional levels of CXCR4 than HSC, conferring them a retention and homing advantage when transplanted i.b.m. Removing HPC and transplanting an HSC-enriched population i.b.m. significantly increased long-term engraftment over i.v. transplantation. Transient upregulation of CXCR4 on GM HSC-enriched cells, using a noncytotoxic portion of viral protein R (VPR) fused to CXCR4 delivered as a protein in lentiviral particles, resulted in higher homing and long-term engraftment of GM HSC transplanted either i.v. or i.b.m. compared with standard i.v. transplants. Overall, we show a mechanism for why i.b.m. transplants do not significantly improve long-term engraftment over i.v. transplants. I.b.m. transplantation becomes relevant when an HSC-enriched population is delivered. Alternatively, CXCR4 expression on HSC, when transiently increased using a protein delivery method, improves homing and engraftment specifically of GM HSC.

Authors

Sydney Felker, Archana Shrestha, Jeff Bailey, Devin M Pillis, Dylan Siniard, Punam Malik

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Air-liquid interface culture promotes maturation and allows environmental exposure of pluripotent stem cell–derived alveolar epithelium
Kristine M. Abo, … , Darrell N. Kotton, Andrew A. Wilson
Kristine M. Abo, … , Darrell N. Kotton, Andrew A. Wilson
Published March 22, 2022
Citation Information: JCI Insight. 2022;7(6):e155589. https://doi.org/10.1172/jci.insight.155589.
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Air-liquid interface culture promotes maturation and allows environmental exposure of pluripotent stem cell–derived alveolar epithelium

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Abstract

Type 2 alveolar epithelial cells (AT2s), facultative progenitor cells of the lung alveolus, play a vital role in the biology of the distal lung. In vitro model systems that incorporate human cells, recapitulate the biology of primary AT2s, and interface with the outside environment could serve as useful tools to elucidate functional characteristics of AT2s in homeostasis and disease. We and others recently adapted human induced pluripotent stem cell–derived AT2s (iAT2s) for air-liquid interface (ALI) culture. Here, we comprehensively characterize the effects of ALI culture on iAT2s and benchmark their transcriptional profile relative to both freshly sorted and cultured primary human fetal and adult AT2s. We find that iAT2s cultured at ALI maintain an AT2 phenotype while upregulating expression of transcripts associated with AT2 maturation. We then leverage this platform to assay the effects of exposure to clinically significant, inhaled toxicants including cigarette smoke and electronic cigarette vapor.

Authors

Kristine M. Abo, Julio Sainz de Aja, Jonathan Lindstrom-Vautrin, Konstantinos-Dionysios Alysandratos, Alexsia Richards, Carolina Garcia-de-Alba, Jessie Huang, Olivia T. Hix, Rhiannon B. Werder, Esther Bullitt, Anne Hinds, Isaac Falconer, Carlos Villacorta-Martin, Rudolf Jaenisch, Carla F. Kim, Darrell N. Kotton, Andrew A. Wilson

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Disruption of the crypt niche promotes outgrowth of mutated colorectal tumor stem cells
Stefan Klingler, … , Anthony M.C. Brown, Richard Kolesnick
Stefan Klingler, … , Anthony M.C. Brown, Richard Kolesnick
Published March 8, 2022
Citation Information: JCI Insight. 2022;7(5):e153793. https://doi.org/10.1172/jci.insight.153793.
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Disruption of the crypt niche promotes outgrowth of mutated colorectal tumor stem cells

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Abstract

Recent data establish a logarithmic expansion of leucine rich repeat containing G protein coupled receptor 5–positive (Lgr5+) colonic epithelial stem cells (CESCs) in human colorectal cancer (CRC). Complementary studies using the murine 2-stage azoxymethane–dextran sulfate sodium (AOM-DSS) colitis-associated tumor model indicate early acquisition of Wnt pathway mutations drives CESC expansion during adenoma progression. Here, subdivision of the AOM-DSS model into in vivo and in vitro stages revealed DSS induced physical separation of CESCs from stem cell niche cells and basal lamina, a source of Wnt signals, within hours, disabling the stem cell program. While AOM delivery in vivo under non-adenoma-forming conditions yielded phenotypically normal mucosa and organoids derived thereof, niche injury ex vivo by progressive DSS dose escalation facilitated outgrowth of Wnt-independent dysplastic organoids. These organoids contained 10-fold increased Lgr5+ CESCs with gain-of-function Wnt mutations orthologous to human CRC driver mutations. We posit CRC originates by niche injury–induced outgrowth of normally suppressed mutated stem cells, consistent with models of adaptive oncogenesis.

Authors

Stefan Klingler, Kuo-Shun Hsu, Guoqiang Hua, Maria Laura Martin, Mohammad Adileh, Timour Baslan, Zhigang Zhang, Philip B. Paty, Zvi Fuks, Anthony M.C. Brown, Richard Kolesnick

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Characterization of disease-propagating stem cells responsible for myeloproliferative neoplasm-blast phase
Xiaoli Wang, … , John Mascarenhas, Ronald Hoffman
Xiaoli Wang, … , John Mascarenhas, Ronald Hoffman
Published March 8, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.156534.
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Characterization of disease-propagating stem cells responsible for myeloproliferative neoplasm-blast phase

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Abstract

Chronic myeloproliferative neoplasms (MPN) frequently evolve to a blast phase (BP) that is almost uniformly resistant to induction chemotherapy or hypomethylating agents. We explored the functional properties, genomic architecture, and cell of origin of MPN-BP initiating cells (IC) using a serial NSG mouse xenograft transplantation model. Transplantation of peripheral blood mononuclear cells (MNC) from 7 of 18 patients resulted in a high degree of leukemic cell chimerism and re-created clinical characteristics of human MPN-BP. The function of MPN-BP ICs was not dependent on the presence of JAK2V617F, a driver mutation associated with the initial underlying MPN. By contrast, multiple MPN-BP IC subclones co-existed within MPN-BP MNCs characterized by different myeloid malignancy gene mutations and cytogenetic abnormalities. MPN-BP ICs in 4 patients exhibited extensive proliferative and self-renewal capacity as demonstrated by their ability to recapitulate human MPN-BP in serial recipients. These MPN-BP IC subclones underwent extensive continuous clonal competition within individual xenografts and across multiple generations and their subclonal dynamics were consistent with functional evolution of MPN-BP IC. Finally, we show that MPN-BP ICs originate from not only phenotypically identified hematopoietic stem cells but also lymphoid-myeloid progenitor cells which were each characterized by differences in MPN-BP initiating activity and self-renewal capacity.

Authors

Xiaoli Wang, Raajit K. Rampal, Cing Siang Hu, Joseph Tripodi, Noushin Farnoud, Bruce Petersen, Michael R. Rossi, Minal Patel, Erin McGovern, Vesna Najfeld, Camelia Iancu-Rubin, Min Lu, Andrew Davis, Marina Kremyanskaya, Rona Singer Weinberg, John Mascarenhas, Ronald Hoffman

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MICU1-dependent mitochondrial calcium uptake regulates lung alveolar type 2 cell plasticity and lung regeneration
Mir Ali, … , John W. Elrod, Ying Tian
Mir Ali, … , John W. Elrod, Ying Tian
Published January 20, 2022
Citation Information: JCI Insight. 2022. https://doi.org/10.1172/jci.insight.154447.
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MICU1-dependent mitochondrial calcium uptake regulates lung alveolar type 2 cell plasticity and lung regeneration

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Abstract

Lung alveolar type 2 (AT2) cells are progenitors for alveolar type 1 (AT1) cells. Although many factors regulate AT2 cell plasticity, the role of mitochondrial calcium (mCa2+) uptake in controlling AT2 cells remains unclear. We previously identified that the microRNA family, miR-302, supports lung epithelial progenitor cell proliferation and less differentiated phenotypes during development. Here we report that a sustained elevation of miR-302 in adult AT2 cells decreases AT2-to-AT1 cell differentiation during the Streptococcus pneumoniae induced lung injury repair. We identified that miR-302 targets and represses the expression of mitochondrial Ca2+ uptake 1 (MICU1), which regulates mCa2+ uptake through the mCa2+ uniporter channel by acting as a gatekeeper at low cytosolic Ca2+ levels. Our results reveal a marked increase in MICU1 protein expression and decreased mCa2+ uptake during AT2-to-AT1 cell differentiation in the adult lung. Deletion of Micu1 in AT2 cells reduces AT2-to-AT1 cell differentiation during steady-state tissue maintenance and alveolar epithelial regeneration following bacterial pneumonia. These studies indicate that mCa2+ uptake is extensively modulated during AT2-to-AT1 cell differentiation and that MICU1-dependent mCa2+ uniporter channel gating is a prominent mechanism modulating AT2-to-AT1 cell differentiation.

Authors

Mir Ali, Xiaoying Zhang, Ryan LaCanna, Dhanendra Tomar, John W. Elrod, Ying Tian

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Growth factors with valproic acid restore injury-impaired hearing by promoting neuronal regeneration
Takahiro Wakizono, … , Takashi Nakagawa, Kinichi Nakashima
Takahiro Wakizono, … , Takashi Nakagawa, Kinichi Nakashima
Published November 22, 2021
Citation Information: JCI Insight. 2021;6(22):e139171. https://doi.org/10.1172/jci.insight.139171.
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Growth factors with valproic acid restore injury-impaired hearing by promoting neuronal regeneration

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Abstract

Spiral ganglion neurons (SGNs) are primary auditory neurons in the spiral ganglion that transmit sound information from the inner ear to the brain and play an important role in hearing. Impairment of SGNs causes sensorineural hearing loss (SNHL), and it has been thought until now that SGNs cannot be regenerated once lost. Furthermore, no fundamental therapeutic strategy for SNHL has been established other than inserting devices such as hearing aids and cochlear implants. Here we show that the mouse spiral ganglion contains cells that are able to proliferate and indeed differentiate into neurons in response to injury. We suggest that SRY-box transcription factor 2/SRY-box transcription factor 10–double-positive (Sox2/Sox10–double-positive) Schwann cells sequentially started to proliferate, lost Sox10 expression, and became neurons, although the number of new neurons generated spontaneously was very small. To increase the abundance of new neurons, we treated mice with 2 growth factors in combination with valproic acid, which is known to promote neuronal differentiation and survival. This treatment resulted in a dramatic increase in the number of SGNs, accompanied by a partial recovery of the hearing loss induced by injury. Taken together, our findings offer a step toward developing strategies for treatment of SNHL.

Authors

Takahiro Wakizono, Hideyuki Nakashima, Tetsuro Yasui, Teppei Noda, Kei Aoyagi, Kanako Okada, Yasuhiro Yamada, Takashi Nakagawa, Kinichi Nakashima

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Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells
Magdalena Hinterbrandner, … , Adrian F. Ochsenbein, Carsten Riether
Magdalena Hinterbrandner, … , Adrian F. Ochsenbein, Carsten Riether
Published November 2, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.151797.
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Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells

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Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by cytotoxic CD8+ T cells (CTLs) is still unknown. In this study, we demonstrate that LSCs in chronic myeloid leukemia (CML) can be recognized and killed by CD8+ CTLs in vitro. However, Tregs, which preferentially localized close to CD8+ CTLs in CML bone marrow (BM), protected LSCs from MHC-class I dependent CD8+ CTL-mediated elimination in vivo. BM Tregs in CML were characterized by the selective expression of tumor necrosis factor receptor 4 (Tnfrsf4). Stimulation of Tnfrsf4-signaling did not deplete Tregs but reduced the capacity of Tregs to protect LSCs from CD8+ CTL-mediated killing. In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulator of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost anti-leukemic immunity in CML.

Authors

Magdalena Hinterbrandner, Viviana Rubino, Carina Stoll, Stefan Forster, Noah Schnüriger, Ramin Radpour, Gabriela M. Baerlocher, Adrian F. Ochsenbein, Carsten Riether

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Clinical trial of ABCB5-positive mesenchymal stem cells for recessive dystrophic epidermolysis bullosa
Dimitra Kiritsi, … , Jakub Tolar, Mark A. Kluth
Dimitra Kiritsi, … , Jakub Tolar, Mark A. Kluth
Published October 19, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.151922.
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Clinical trial of ABCB5-positive mesenchymal stem cells for recessive dystrophic epidermolysis bullosa

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Abstract

BACKGROUND. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5-positive dermal mesenchymal stem cells (ABCB5+ MSCs) possess immunomodulatory capacities, a favorable skin homing potential and the ability to secrete type VII collagen. In a COL7A1–/– mouse model of RDEB, treatment with ABCB5+ MSCs markedly extended the animals’ lifespans. METHODS. In this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4–36 years) enrolled into four age cohorts received three intravenous infusions of 2×106 ABCB5+ MSCs/kg on days 0, 17 and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety. RESULTS. At 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%-30%; P = 0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB c) score of 18.2% (4.1%-41.7%; P = 0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%-42.9%; P = 0.033) and 25.0% (-8.4%-46.4%; P = 0.168), respectively. Three adverse events were considered related to the cell product, one mild lymphadenopathy and two hypersensitivity reactions. The latter two were serious but resolved without sequelae shortly after withdrawal of treatment. CONCLUSION. This trial demonstrates good tolerability, manageable safety and potential efficacy of intravenous ABCB5+ MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation. TRIAL REGISTRATION. clinicaltrials.gov NCT03529877; EudraCT 2018-001009-98 FUNDING. The trial was sponsored by RHEACELL GmbH & Co. KG, Heidelberg, Germany. Contributions by NY Frank and MH Frank to this work were supported by the National Institutes of Health (NIH)/National Eye Institute (NEI) grants RO1EY025794 and R24EY028767.

Authors

Dimitra Kiritsi, Kathrin Dieter, Elke Niebergall-Roth, Silvia Fluhr, Cristina Daniele, Jasmina Esterlechner, Samar Sadeghi, Seda Ballikaya, Leoni Erdinger, Franziska Schauer, Stella Gewert, Martin Laimer, Johann W. Bauer, Alain Hovnanian, Giovanna Zambruno, May El Hachem, Emmanuelle Bourrat, Maria Papanikolaou, Gabriela Petrof, Sophie Kitzmüller, Christen L. Ebens, Markus H. Frank, Natasha Y. Frank, Christoph Ganss, Anna E. Martinez, John A. McGrath, Jakub Tolar, Mark A. Kluth

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Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells
Costanza Lo Cascio, … , Christopher L. Plaisier, Shwetal Mehta
Costanza Lo Cascio, … , Christopher L. Plaisier, Shwetal Mehta
Published September 8, 2021
Citation Information: JCI Insight. 2021;6(17):e149232. https://doi.org/10.1172/jci.insight.149232.
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Nonredundant, isoform-specific roles of HDAC1 in glioma stem cells

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Abstract

Glioblastoma (GBM) is characterized by an aberrant yet druggable epigenetic landscape. One major family of epigenetic regulators, the histone deacetylases (HDACs), are considered promising therapeutic targets for GBM due to their repressive influences on transcription. Although HDACs share redundant functions and common substrates, the unique isoform-specific roles of different HDACs in GBM remain unclear. In neural stem cells, HDAC2 is the indispensable deacetylase to ensure normal brain development and survival in the absence of HDAC1. Surprisingly, we find that HDAC1 is the essential class I deacetylase in glioma stem cells, and its loss is not compensated for by HDAC2. Using cell-based and biochemical assays, transcriptomic analyses, and patient-derived xenograft models, we find that knockdown of HDAC1 alone has profound effects on the glioma stem cell phenotype in a p53-dependent manner. We demonstrate marked suppression in tumor growth upon targeting of HDAC1 and identify compensatory pathways that provide insights into combination therapies for GBM. Our study highlights the importance of HDAC1 in GBM and the need to develop isoform-specific drugs.

Authors

Costanza Lo Cascio, James B. McNamara, Ernesto L. Melendez, Erika M. Lewis, Matthew E. Dufault, Nader Sanai, Christopher L. Plaisier, Shwetal Mehta

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In vivo grafting of large engineered heart tissue patches for cardiac repair
Richard J. Jabbour, … , Thomas Eschenhagen, Sian E. Harding
Richard J. Jabbour, … , Thomas Eschenhagen, Sian E. Harding
Published August 9, 2021
Citation Information: JCI Insight. 2021;6(15):e144068. https://doi.org/10.1172/jci.insight.144068.
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In vivo grafting of large engineered heart tissue patches for cardiac repair

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Abstract

Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be a novel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more data are needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5 mm) consisting of up to 20 million human induced pluripotent stem cell–derived cardiomyocytes (hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarction model was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs in EHTs became more aligned over 28 days and had improved contraction kinetics and faster calcium transients. Blinded echocardiographic analysis revealed a significant improvement in function in infarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularization from the host to the patch was observed at week 1 and stable to week 4, but electrical coupling between patch and host heart was not observed. In vivo telemetry recordings and ex vivo arrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTs improved function and reduced scar size without causing arrhythmia, which may be due to the lack of electrical coupling between patch and host heart.

Authors

Richard J. Jabbour, Thomas J. Owen, Pragati Pandey, Marina Reinsch, Brian Wang, Oisín King, Liam Steven Couch, Dafni Pantou, David S. Pitcher, Rasheda A. Chowdhury, Fotios G. Pitoulis, Balvinder S. Handa, Worrapong Kit-Anan, Filippo Perbellini, Rachel C. Myles, Daniel J. Stuckey, Michael Dunne, Mayooran Shanmuganathan, Nicholas S. Peters, Fu Siong Ng, Florian Weinberger, Cesare M. Terracciano, Godfrey L. Smith, Thomas Eschenhagen, Sian E. Harding

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