innsikt - Developmental biology - # Necrosis-induced Apoptosis (NiA) and Regenerative Proliferation in Drosophila Wing Discs

Necrosis-Induced Caspase Activation Promotes Regenerative Proliferation in Drosophila Wing Discs

Q: How might the insights from this study on NiA-driven regeneration in Drosophila inform strategies for enhancing tissue repair in human diseases involving necrosis, such as ischemic injuries?

The study on Necrosis-induced Apoptosis (NiA) in Drosophila provides valuable insights that could inform therapeutic strategies for enhancing tissue repair in human diseases characterized by necrosis, such as ischemic injuries. One of the key findings is that NiA facilitates regeneration through non-apoptotic caspase activity, which promotes localized proliferation in response to necrotic damage. This suggests that harnessing similar mechanisms in human tissues could enhance regenerative responses following ischemic events. In human contexts, strategies could be developed to stimulate non-apoptotic caspase pathways or mimic the signaling events observed in Drosophila. For instance, targeting the Dronc homologs in mammals may activate similar regenerative pathways without triggering apoptosis, thereby preserving cell viability while promoting tissue repair. Additionally, understanding the role of Damage-Associated Molecular Patterns (DAMPs) released during necrosis could lead to the development of therapies that enhance the recruitment of repair cells or modulate inflammatory responses, ultimately improving healing outcomes. Furthermore, the spatial regulation of NiA by WNT and JAK/STAT signaling pathways highlights the potential for manipulating these pathways in human tissues to enhance regeneration. For example, pharmacological agents that modulate WNT signaling could be explored to promote regenerative proliferation in areas affected by ischemic damage. Overall, the insights from this study could pave the way for innovative approaches to enhance tissue repair mechanisms in human diseases involving necrosis.

Q: What other signaling pathways or genetic factors, beyond WNT and JAK/STAT, might regulate the spatial patterning and persistence of NiA cells to modulate their proliferative effects during regeneration?

Beyond WNT and JAK/STAT signaling pathways, several other signaling pathways and genetic factors could play a role in regulating the spatial patterning and persistence of NiA cells during regeneration. For instance, the Hippo signaling pathway, known for its role in regulating cell growth and proliferation, may influence the behavior of NiA cells. The Hippo pathway's interaction with the YAP/TAZ transcriptional co-activators could modulate the balance between cell proliferation and apoptosis, potentially affecting the regenerative capacity of tissues. Additionally, the Notch signaling pathway, which is crucial for cell fate determination and tissue homeostasis, might also impact NiA cell dynamics. Notch signaling can influence the proliferation and differentiation of neighboring cells, thereby shaping the regenerative response in the context of necrosis. Moreover, the role of inflammatory signaling pathways, such as NF-κB and TNF-α signaling, could be significant in modulating the persistence of NiA cells. These pathways are known to regulate immune responses and tissue repair processes, and their interaction with DAMPs released during necrosis could further influence the spatial distribution and activity of NiA cells. Lastly, the involvement of extracellular matrix (ECM) components and their signaling could also be critical. ECM remodeling factors may provide the necessary cues for NiA cells to persist and proliferate in specific regions, thereby enhancing the overall regenerative response. Investigating these additional pathways and factors could provide a more comprehensive understanding of the regulatory networks governing NiA and its role in tissue regeneration.

Q: Could the non-apoptotic, Dronc-dependent proliferative mechanism uncovered in this study have broader relevance beyond the wing disc, potentially playing a role in regeneration or homeostasis in other Drosophila or even mammalian tissues?

The non-apoptotic, Dronc-dependent proliferative mechanism identified in this study has the potential for broader relevance beyond the Drosophila wing disc, possibly influencing regeneration and homeostasis in other Drosophila tissues and even in mammalian systems. The conservation of caspase signaling pathways across species suggests that similar mechanisms may operate in various contexts of tissue repair and regeneration. In Drosophila, other tissues such as the eye, gut, and muscle may exhibit analogous responses to necrotic damage, where non-apoptotic caspase activity could promote proliferation and tissue regeneration. For instance, in the Drosophila gut, the interplay between cell death and regeneration is critical for maintaining homeostasis, and the insights from NiA could inform how caspase signaling influences these processes. In mammals, the concept of non-apoptotic caspase signaling is gaining traction, particularly in the context of tissue repair following injury. The role of caspases in promoting cell proliferation and survival in various tissues, including the heart and liver, suggests that similar Dronc-dependent mechanisms could be at play. Understanding how non-apoptotic caspase activity contributes to regenerative processes in mammals could lead to novel therapeutic strategies aimed at enhancing tissue repair in conditions such as myocardial infarction or liver damage. Overall, the findings from this study underscore the importance of exploring non-apoptotic signaling pathways in regeneration, as they may offer new avenues for therapeutic intervention in both Drosophila and mammalian systems.

Grunnleggende konsepter

Necrosis-induced caspase activation in cells distant from the injury site (NiA) promotes regenerative proliferation in the Drosophila wing disc through a novel non-apoptotic function of the initiator caspase Dronc, independent of established Apoptosis-induced Proliferation (AiP) mechanisms.

Sammendrag

The study investigates the genetic response to tissue necrosis and its impact on regeneration in the Drosophila wing imaginal disc. Key findings:

NiA formation is predominantly restricted to the highly regenerative wing pouch region, regulated by WNT and JAK/STAT signaling pathways that limit NiA in the less regenerative hinge region.
NiA cells persist late into the regeneration process (up to 64 hours) and promote a significant increase in proliferation across the pouch at 36-48 hours post-injury, distinct from the early proliferative response driven by apoptosis at the wound edge.
This late-stage proliferation relies on the initiator caspase Dronc, but occurs independently of the Apoptosis-induced Proliferation (AiP) mechanisms involving mitogen production and ROS signaling.
A subset of NiA cells survive effector caspase activation and maintain markers of both DNA repair and proliferation, suggesting they directly stimulate the late regenerative proliferative response.

Together, these findings reveal a novel non-apoptotic function of caspases in promoting regeneration following necrotic injury, which could have implications for understanding and potentially enhancing regenerative capacity in human diseases involving tissue necrosis.

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biorxiv.org

Statistikk

Necrosis of the entire wing pouch results in significant Dcp-1 (cleaved caspase) positive cells, many of which also express the JNK target Mmp1, indicating JNK-mediated apoptosis rather than NiA.
Necrosis of the notum or hinge regions does not induce NiA in the neighboring pouch cells.
Blocking apoptosis in either the wound edge or lateral pouch regions reduces the late-stage (36 hour) proliferative response following necrotic injury.

Sitater

"NiA is predominantly associated with the highly regenerative pouch region of the disc, shaped by genetic factors present in the presumptive hinge."
"A proportion of NiA fail to undergo apoptosis, instead surviving effector caspase activation to persist within the tissue and stimulate reparative proliferation late in regeneration."
"This proliferation relies on the initiator caspase Dronc, and occurs independent of JNK, ROS or mitogens associated with the previously characterized Apoptosis-induced Proliferation (AiP) mechanism."

Viktige innsikter hentet fra

Regeneration following tissue necrosis is mediated by non-apoptotic caspase activity

by Klemm,J., Va... klokken www.biorxiv.org 07-26-2024

https://www.biorxiv.org/content/10.1101/2024.07.26.605350v1

Dypere Spørsmål

How might the insights from this study on NiA-driven regeneration in Drosophila inform strategies for enhancing tissue repair in human diseases involving necrosis, such as ischemic injuries?

The study on Necrosis-induced Apoptosis (NiA) in Drosophila provides valuable insights that could inform therapeutic strategies for enhancing tissue repair in human diseases characterized by necrosis, such as ischemic injuries. One of the key findings is that NiA facilitates regeneration through non-apoptotic caspase activity, which promotes localized proliferation in response to necrotic damage. This suggests that harnessing similar mechanisms in human tissues could enhance regenerative responses following ischemic events.
In human contexts, strategies could be developed to stimulate non-apoptotic caspase pathways or mimic the signaling events observed in Drosophila. For instance, targeting the Dronc homologs in mammals may activate similar regenerative pathways without triggering apoptosis, thereby preserving cell viability while promoting tissue repair. Additionally, understanding the role of Damage-Associated Molecular Patterns (DAMPs) released during necrosis could lead to the development of therapies that enhance the recruitment of repair cells or modulate inflammatory responses, ultimately improving healing outcomes.
Furthermore, the spatial regulation of NiA by WNT and JAK/STAT signaling pathways highlights the potential for manipulating these pathways in human tissues to enhance regeneration. For example, pharmacological agents that modulate WNT signaling could be explored to promote regenerative proliferation in areas affected by ischemic damage. Overall, the insights from this study could pave the way for innovative approaches to enhance tissue repair mechanisms in human diseases involving necrosis.

What other signaling pathways or genetic factors, beyond WNT and JAK/STAT, might regulate the spatial patterning and persistence of NiA cells to modulate their proliferative effects during regeneration?

Beyond WNT and JAK/STAT signaling pathways, several other signaling pathways and genetic factors could play a role in regulating the spatial patterning and persistence of NiA cells during regeneration. For instance, the Hippo signaling pathway, known for its role in regulating cell growth and proliferation, may influence the behavior of NiA cells. The Hippo pathway's interaction with the YAP/TAZ transcriptional co-activators could modulate the balance between cell proliferation and apoptosis, potentially affecting the regenerative capacity of tissues.
Additionally, the Notch signaling pathway, which is crucial for cell fate determination and tissue homeostasis, might also impact NiA cell dynamics. Notch signaling can influence the proliferation and differentiation of neighboring cells, thereby shaping the regenerative response in the context of necrosis.
Moreover, the role of inflammatory signaling pathways, such as NF-κB and TNF-α signaling, could be significant in modulating the persistence of NiA cells. These pathways are known to regulate immune responses and tissue repair processes, and their interaction with DAMPs released during necrosis could further influence the spatial distribution and activity of NiA cells.
Lastly, the involvement of extracellular matrix (ECM) components and their signaling could also be critical. ECM remodeling factors may provide the necessary cues for NiA cells to persist and proliferate in specific regions, thereby enhancing the overall regenerative response. Investigating these additional pathways and factors could provide a more comprehensive understanding of the regulatory networks governing NiA and its role in tissue regeneration.

Could the non-apoptotic, Dronc-dependent proliferative mechanism uncovered in this study have broader relevance beyond the wing disc, potentially playing a role in regeneration or homeostasis in other Drosophila or even mammalian tissues?

The non-apoptotic, Dronc-dependent proliferative mechanism identified in this study has the potential for broader relevance beyond the Drosophila wing disc, possibly influencing regeneration and homeostasis in other Drosophila tissues and even in mammalian systems. The conservation of caspase signaling pathways across species suggests that similar mechanisms may operate in various contexts of tissue repair and regeneration.
In Drosophila, other tissues such as the eye, gut, and muscle may exhibit analogous responses to necrotic damage, where non-apoptotic caspase activity could promote proliferation and tissue regeneration. For instance, in the Drosophila gut, the interplay between cell death and regeneration is critical for maintaining homeostasis, and the insights from NiA could inform how caspase signaling influences these processes.
In mammals, the concept of non-apoptotic caspase signaling is gaining traction, particularly in the context of tissue repair following injury. The role of caspases in promoting cell proliferation and survival in various tissues, including the heart and liver, suggests that similar Dronc-dependent mechanisms could be at play. Understanding how non-apoptotic caspase activity contributes to regenerative processes in mammals could lead to novel therapeutic strategies aimed at enhancing tissue repair in conditions such as myocardial infarction or liver damage.
Overall, the findings from this study underscore the importance of exploring non-apoptotic signaling pathways in regeneration, as they may offer new avenues for therapeutic intervention in both Drosophila and mammalian systems.