Designer Stem Cells: Genome Engineering and the Next Generation of Cell‐Based Therapies

Guilak, Farshid; Pferdehirt, Lara; Ross, Alison K.; Choi, Yun Rak; Collins, KelseyH; Nims, Robert J.; Katz, Dakota B; Klimak, Molly; Tabbaa, Suzanne M.; Pham, Christine

doi:10.1002/jor.24304

Cited by 28 publications

(12 citation statements)

References 70 publications

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“…Deep RNA sequencing and promotor engineering may provide a unique strategy for developing distinct, mechanoresponsive tools in an inflammatory, osteoarthritic joint. Additional therapeutic targets can also be readily inhibited or activated as well; our laboratory has investigated using intracellular inhibitors of NF-B signaling and the soluble tumor necrosis factor receptor-1 as two alternative options for inhibiting inflammation (59,60).…”

Section: Discussionmentioning

confidence: 99%

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues

Nims

Pferdehirt

et al. 2021

Sci. Adv.

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Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically responsive bioartificial tissue that responds to mechanical loading to produce a preprogrammed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not by direct cellular deformation, suggesting that tissue loading is transduced into an osmotic signal that activates TRPV4. Either osmotic or mechanical loading of tissues transduced with TRPV4-responsive circuits protected constructs from inflammatory degradation by interleukin-1α. This synthetic mechanobiology approach was used to develop a mechanogenetic system to enable long-term, autonomously regulated drug delivery driven by physiologically relevant loading.

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Section: Discussionmentioning

confidence: 99%

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues

Nims

Pferdehirt

et al. 2021

Sci. Adv.

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“…Furthermore, subject-specific numerical models can be helpful in optimization of personalized intervention strategies, rehabilitation procedures, and surgeries. They could also be salutary in development of immunomodulating therapies [22,23] and disease-modifying osteoarthritis drugs [9,24,25]. When validated with experimental data, mechanobiological models can provide key quantitative and qualitative insights into biochemical and biomechanical adaptive processes in cartilage.…”

Section: Introductionmentioning

confidence: 99%

“…Some cytokines in cartilage are pro-anabolic (anti-inflammatory), such as transforming growth factor beta (TGF-β), interleukin (IL)-1 receptor antagonist, IL-4, IL-10, and erythropoietin [ 22 , 28 , 32 ]. Other cytokines are pro-catabolic (pro-inflammatory), such as tumor necrosis factor alpha (TNFα), IL-1, IL-6, IL-8, IL-12, and IL-15 [ 3 , 8 , 23 , 33 , 34 ]. Previous experiments [ 4 , 35 – 37 ] suggest that chondrocytes affected by pro-inflammatory cytokines upregulate production of proteolytic aggrecanases ADAMTS-4,5 (a-disintegrin and metalloproteinase with thrombospondin motifs-4,5) and matrix metalloproteinases including the collagenases MMP-1,13.…”

Section: Introductionmentioning

confidence: 99%

Mechanobiological model for simulation of injured cartilage degradation via pro-inflammatory cytokines and mechanical stimulus

et al. 2020

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Post-traumatic osteoarthritis (PTOA) is associated with cartilage degradation, ultimately leading to disability and decrease of quality of life. Two key mechanisms have been suggested to occur in PTOA: tissue inflammation and abnormal biomechanical loading. Both mechanisms have been suggested to result in loss of cartilage proteoglycans, the source of tissue fixed charge density (FCD). In order to predict the simultaneous effect of these degrading mechanisms on FCD content, a computational model has been developed. We simulated spatial and temporal changes of FCD content in injured cartilage using a novel finite element model that incorporates (1) diffusion of the pro-inflammatory cytokine interleukin-1 into tissue, and (2) the effect of excessive levels of shear strain near chondral defects during physiologically relevant loading. Cytokine-induced biochemical cartilage explant degradation occurs near the sides, top, and lesion, consistent with the literature. In turn, biomechanically-driven FCD loss is predicted near the lesion, in accordance with experimental findings: regions near lesions showed significantly more FCD depletion compared to regions away from lesions (p<0.01). Combined biochemical and biomechanical degradation is found near the free surfaces and especially near the lesion, and the corresponding bulk FCD loss agrees with experiments. We suggest that the presence of lesions plays a role in cytokine diffusion-driven degradation, and also predisposes cartilage for further biomechanical degradation. Models considering both these cartilage degradation pathways concomitantly are promising in silico tools for predicting disease progression, recognizing lesions at high risk, simulating treatments, and ultimately optimizing treatments to postpone the development of PTOA.

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“…Chondrocytes originate from mesenchymal stem cells [ 71 , 72 ]. Bone-marrow-derived MSCs (BM-MSCs) have much promise in aiding articular cartilage repair due to their proximity to the joint, high differentiation capability, and ability to secrete different growth, anti-inflammatory, and immunomodulatory factors [ 73 , 74 , 75 , 76 , 77 ]. They could affect a clinically relevant improvement in joint pain and function.…”

Section: Mesenchymal Stem Cells and Tissue Regenerationmentioning

confidence: 99%

Emerging Gene-Editing Modalities for Osteoarthritis

Tanikella

Hardy

Frahs

et al. 2020

IJMS

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Osteoarthritis (OA) is a pathological degenerative condition of the joints that is widely prevalent worldwide, resulting in significant pain, disability, and impaired quality of life. The diverse etiology and pathogenesis of OA can explain the paucity of viable preventive and disease-modifying strategies to counter it. Advances in genome-editing techniques may improve disease-modifying solutions by addressing inherited predisposing risk factors and the activity of inflammatory modulators. Recent progress on technologies such as CRISPR/Cas9 and cell-based genome-editing therapies targeting the genetic and epigenetic alternations in OA offer promising avenues for early diagnosis and the development of personalized therapies. The purpose of this literature review was to concisely summarize the genome-editing options against chronic degenerative joint conditions such as OA with a focus on the more recently emerging modalities, especially CRISPR/Cas9. Future advancements in novel genome-editing therapies may improve the efficacy of such targeted treatments.

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Designer Stem Cells: Genome Engineering and the Next Generation of Cell‐Based Therapies

Cited by 28 publications

References 70 publications

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues

Mechanobiological model for simulation of injured cartilage degradation via pro-inflammatory cytokines and mechanical stimulus

Emerging Gene-Editing Modalities for Osteoarthritis

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