Therapeutic intersections: Expanding benefits of CD19 CAR T cells from cancer to autoimmunity
Cell Stem Cell. 2024 Apr 4;31(4):437-438. doi: 10.1016/j.stem.2024.03.006.ABSTRACTAnti-CD19 CAR T cells were among the last decade's scientific breakthroughs, achieving remarkable remissions in patients with B cell leukemias and lymphomas. Now, the engineered cell therapies are traversing disease indications into autoimmunity and resolving disease symptoms in patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis.1.PMID:38579681 | DOI:10.1016/j.stem.2024.03.006 (Source: Cell Stem Cell)
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Heather M Sosnoski Avery D Posey Source Type: research
A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection
We describe a targeted Cas9/AAV6-based genome editing strategy for autologous HSCT resulting in both CCR5- and CXCR4-tropic HIV-1 resistance. Edited human hematopoietic stem and progenitor cells (HSPCs) maintain multi-lineage repopulation capacity in vivo, and edited primary human T cells potently inhibit infection by both CCR5-tropic and CXCR4-tropic HIV-1. Modification rates facilitated complete loss of CCR5-tropic replication and up to a 2,000-fold decrease in CXCR4-tropic replication without CXCR4 locus disruption. This multi-factor editing strategy in HSPCs could provide a broad approach for autologous HSCT as a funct...
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Amanda M Dudek William N Feist Elena J Sasu Sofia E Luna Kaya Ben-Efraim Rasmus O Bak Alma-Martina Cepika Matthew H Porteus Source Type: research
KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury
Cell Stem Cell. 2024 Apr 4;31(4):519-536.e8. doi: 10.1016/j.stem.2024.03.004.ABSTRACTTraumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neu...
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Jesse D Lai Joshua E Berlind Gabriella Fricklas Cecilia Lie Jean-Paul Urenda Kelsey Lam Naomi Sta Maria Russell Jacobs Violeta Yu Zhen Zhao Justin K Ichida Source Type: research
Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease
Cell Stem Cell. 2024 Apr 4;31(4):537-553.e5. doi: 10.1016/j.stem.2024.03.005.ABSTRACTIn polycystic kidney disease (PKD), microscopic tubules expand into macroscopic cysts. Among the world's most common genetic disorders, PKD is inherited via heterozygous loss-of-function mutations but is theorized to require additional loss of function. To test this, we establish human pluripotent stem cells in allelic series representing four common nonsense mutations, using CRISPR base editing. When differentiated into kidney organoids, homozygous mutants spontaneously form cysts, whereas heterozygous mutants (original or base corrected)...
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Courtney E Vishy Chardai Thomas Thomas Vincent Daniel K Crawford Matthew M Goddeeris Benjamin S Freedman Source Type: research
NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo
Cell Stem Cell. 2024 Apr 4;31(4):554-569.e17. doi: 10.1016/j.stem.2024.03.003.ABSTRACTThe YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIB...
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Kenji Namoto Clara Baader Vanessa Orsini Alexandro Landshammer Eva Breuer Kieu Trinh Dinh Rosemarie Ungricht Monika Pikiolek Stephane Laurent Bo Lu Alexandra Aebi Katharina Sch önberger Eric Vangrevelinghe Olivera Evrova Tianliang Sun Stefano Annunziato Source Type: research
Genetic haute couture to block HIV-1 at front doors
Cell Stem Cell. 2024 Apr 4;31(4):433-434. doi: 10.1016/j.stem.2024.03.009.ABSTRACTThe chemokine receptors CCR5 and CXCR4 are "front doors" for HIV-1 infection in host cells, and their targeting represents a potential solution for a cure. Dudek et al.1 now propose a new gene editing strategy to simultaneously block CCR5- and CXCR4-mediated HIV-1 entry in autologous hematopoietic stem and progenitor cells (HSPCs).PMID:38579679 | DOI:10.1016/j.stem.2024.03.009 (Source: Cell Stem Cell)
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Petronela Ancuta Source Type: research
The difficult translational pathway from animal models to patients
Cell Stem Cell. 2024 Apr 4;31(4):435-436. doi: 10.1016/j.stem.2024.03.010.ABSTRACTLee et al.1 analyzed the impacts of lentiviral vector transduction and CRISPR-Cas9/homology-directed repair editing on hematopoietic stem and progenitor cell (HSPC) engraftment and clonal dynamics. The study suggests that relative to lentiviral-vector-mediated gene addition, homology-directed repair editing is inefficient in vivo and might impair the engraftment and differentiation of HSPCs.PMID:38579680 | DOI:10.1016/j.stem.2024.03.010 (Source: Cell Stem Cell)
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Marina Cavazzana Annarita Miccio Source Type: research
Therapeutic intersections: Expanding benefits of CD19 CAR T cells from cancer to autoimmunity
Cell Stem Cell. 2024 Apr 4;31(4):437-438. doi: 10.1016/j.stem.2024.03.006.ABSTRACTAnti-CD19 CAR T cells were among the last decade's scientific breakthroughs, achieving remarkable remissions in patients with B cell leukemias and lymphomas. Now, the engineered cell therapies are traversing disease indications into autoimmunity and resolving disease symptoms in patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis.1.PMID:38579681 | DOI:10.1016/j.stem.2024.03.006 (Source: Cell Stem Cell)
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Heather M Sosnoski Avery D Posey Source Type: research
A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection
We describe a targeted Cas9/AAV6-based genome editing strategy for autologous HSCT resulting in both CCR5- and CXCR4-tropic HIV-1 resistance. Edited human hematopoietic stem and progenitor cells (HSPCs) maintain multi-lineage repopulation capacity in vivo, and edited primary human T cells potently inhibit infection by both CCR5-tropic and CXCR4-tropic HIV-1. Modification rates facilitated complete loss of CCR5-tropic replication and up to a 2,000-fold decrease in CXCR4-tropic replication without CXCR4 locus disruption. This multi-factor editing strategy in HSPCs could provide a broad approach for autologous HSCT as a funct...
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Amanda M Dudek William N Feist Elena J Sasu Sofia E Luna Kaya Ben-Efraim Rasmus O Bak Alma-Martina Cepika Matthew H Porteus Source Type: research
KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury
Cell Stem Cell. 2024 Apr 4;31(4):519-536.e8. doi: 10.1016/j.stem.2024.03.004.ABSTRACTTraumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neu...
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Jesse D Lai Joshua E Berlind Gabriella Fricklas Cecilia Lie Jean-Paul Urenda Kelsey Lam Naomi Sta Maria Russell Jacobs Violeta Yu Zhen Zhao Justin K Ichida Source Type: research
Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease
Cell Stem Cell. 2024 Apr 4;31(4):537-553.e5. doi: 10.1016/j.stem.2024.03.005.ABSTRACTIn polycystic kidney disease (PKD), microscopic tubules expand into macroscopic cysts. Among the world's most common genetic disorders, PKD is inherited via heterozygous loss-of-function mutations but is theorized to require additional loss of function. To test this, we establish human pluripotent stem cells in allelic series representing four common nonsense mutations, using CRISPR base editing. When differentiated into kidney organoids, homozygous mutants spontaneously form cysts, whereas heterozygous mutants (original or base corrected)...
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Courtney E Vishy Chardai Thomas Thomas Vincent Daniel K Crawford Matthew M Goddeeris Benjamin S Freedman Source Type: research
NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo
Cell Stem Cell. 2024 Apr 4;31(4):554-569.e17. doi: 10.1016/j.stem.2024.03.003.ABSTRACTThe YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIB...
Source: Cell Stem Cell - April 5, 2024 Category: Stem Cells Authors: Kenji Namoto Clara Baader Vanessa Orsini Alexandro Landshammer Eva Breuer Kieu Trinh Dinh Rosemarie Ungricht Monika Pikiolek Stephane Laurent Bo Lu Alexandra Aebi Katharina Sch önberger Eric Vangrevelinghe Olivera Evrova Tianliang Sun Stefano Annunziato Source Type: research
Harnessing developmental dynamics of spinal cord extracellular matrix improves regenerative potential of spinal cord organoids
Cell Stem Cell. 2024 Mar 26:S1934-5909(24)00089-4. doi: 10.1016/j.stem.2024.03.007. Online ahead of print.ABSTRACTNeonatal spinal cord tissues exhibit remarkable regenerative capabilities as compared to adult spinal cord tissues after injury, but the role of extracellular matrix (ECM) in this process has remained elusive. Here, we found that early developmental spinal cord had higher levels of ECM proteins associated with neural development and axon growth, but fewer inhibitory proteoglycans, compared to those of adult spinal cord. Decellularized spinal cord ECM from neonatal (DNSCM) and adult (DASCM) rabbits preserved the...
Source: Cell Stem Cell - April 2, 2024 Category: Stem Cells Authors: Zheng Sun Zhenni Chen Man Yin Xianming Wu Bo Guo Xiaokang Cheng Rui Quan Yuting Sun Qi Zhang Yongheng Fan Chen Jin Yanyun Yin Xianglin Hou Weiyuan Liu Muya Shu Xiaoyu Xue Ya Shi Bing Chen Zhifeng Xiao Jianwu Dai Yannan Zhao Source Type: research
Harnessing developmental dynamics of spinal cord extracellular matrix improves regenerative potential of spinal cord organoids
Cell Stem Cell. 2024 Mar 26:S1934-5909(24)00089-4. doi: 10.1016/j.stem.2024.03.007. Online ahead of print.ABSTRACTNeonatal spinal cord tissues exhibit remarkable regenerative capabilities as compared to adult spinal cord tissues after injury, but the role of extracellular matrix (ECM) in this process has remained elusive. Here, we found that early developmental spinal cord had higher levels of ECM proteins associated with neural development and axon growth, but fewer inhibitory proteoglycans, compared to those of adult spinal cord. Decellularized spinal cord ECM from neonatal (DNSCM) and adult (DASCM) rabbits preserved the...
Source: Cell Stem Cell - April 2, 2024 Category: Stem Cells Authors: Zheng Sun Zhenni Chen Man Yin Xianming Wu Bo Guo Xiaokang Cheng Rui Quan Yuting Sun Qi Zhang Yongheng Fan Chen Jin Yanyun Yin Xianglin Hou Weiyuan Liu Muya Shu Xiaoyu Xue Ya Shi Bing Chen Zhifeng Xiao Jianwu Dai Yannan Zhao Source Type: research
Harnessing developmental dynamics of spinal cord extracellular matrix improves regenerative potential of spinal cord organoids
Cell Stem Cell. 2024 Mar 26:S1934-5909(24)00089-4. doi: 10.1016/j.stem.2024.03.007. Online ahead of print.ABSTRACTNeonatal spinal cord tissues exhibit remarkable regenerative capabilities as compared to adult spinal cord tissues after injury, but the role of extracellular matrix (ECM) in this process has remained elusive. Here, we found that early developmental spinal cord had higher levels of ECM proteins associated with neural development and axon growth, but fewer inhibitory proteoglycans, compared to those of adult spinal cord. Decellularized spinal cord ECM from neonatal (DNSCM) and adult (DASCM) rabbits preserved the...
Source: Cell Stem Cell - April 2, 2024 Category: Stem Cells Authors: Zheng Sun Zhenni Chen Man Yin Xianming Wu Bo Guo Xiaokang Cheng Rui Quan Yuting Sun Qi Zhang Yongheng Fan Chen Jin Yanyun Yin Xianglin Hou Weiyuan Liu Muya Shu Xiaoyu Xue Ya Shi Bing Chen Zhifeng Xiao Jianwu Dai Yannan Zhao Source Type: research
