Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function

Michael J. White, Simone M. Schoenwaelder, Emma C. Josefsson, Kate E. Jarman, Katya J. Henley, Chloe James, Marlyse A. Debrincat, Shaun P. Jackson, David C. S. Huang, Benjamin T. Kile

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54 Citations (Scopus)

Abstract

Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737a??induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9a??/a?? platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function.
Original languageEnglish
Article number18
Pages (from-to)4283-4290
Number of pages8
JournalBlood
Volume119
Issue number18
DOIs
Publication statusPublished - 3 May 2012

Cite this

White, M. J., Schoenwaelder, S. M., Josefsson, E. C., Jarman, K. E., Henley, K. J., James, C., ... Kile, B. T. (2012). Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function. Blood, 119(18), 4283-4290. [18]. https://doi.org/10.1182/blood-2011-11-394858
White, Michael J. ; Schoenwaelder, Simone M. ; Josefsson, Emma C. ; Jarman, Kate E. ; Henley, Katya J. ; James, Chloe ; Debrincat, Marlyse A. ; Jackson, Shaun P. ; Huang, David C. S. ; Kile, Benjamin T. / Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function. In: Blood. 2012 ; Vol. 119, No. 18. pp. 4283-4290.
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title = "Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function",
abstract = "Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737a??induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9a??/a?? platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function.",
author = "White, {Michael J.} and Schoenwaelder, {Simone M.} and Josefsson, {Emma C.} and Jarman, {Kate E.} and Henley, {Katya J.} and Chloe James and Debrincat, {Marlyse A.} and Jackson, {Shaun P.} and Huang, {David C. S.} and Kile, {Benjamin T.}",
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White, MJ, Schoenwaelder, SM, Josefsson, EC, Jarman, KE, Henley, KJ, James, C, Debrincat, MA, Jackson, SP, Huang, DCS & Kile, BT 2012, 'Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function', Blood, vol. 119, no. 18, 18, pp. 4283-4290. https://doi.org/10.1182/blood-2011-11-394858

Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function. / White, Michael J.; Schoenwaelder, Simone M.; Josefsson, Emma C.; Jarman, Kate E.; Henley, Katya J.; James, Chloe; Debrincat, Marlyse A.; Jackson, Shaun P.; Huang, David C. S.; Kile, Benjamin T.

In: Blood, Vol. 119, No. 18, 18, 03.05.2012, p. 4283-4290.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function

AU - White, Michael J.

AU - Schoenwaelder, Simone M.

AU - Josefsson, Emma C.

AU - Jarman, Kate E.

AU - Henley, Katya J.

AU - James, Chloe

AU - Debrincat, Marlyse A.

AU - Jackson, Shaun P.

AU - Huang, David C. S.

AU - Kile, Benjamin T.

PY - 2012/5/3

Y1 - 2012/5/3

N2 - Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737a??induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9a??/a?? platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function.

AB - Apoptotic caspases, including caspase-9, are thought to facilitate platelet shedding by megakaryocytes. They are known to be activated during platelet apoptosis, and have also been implicated in platelet hemostatic responses. However, the precise requirement for, and the regulation of, apoptotic caspases have never been defined in either megakaryocytes or platelets. To establish the role of caspases in platelet production and function, we generated mice lacking caspase-9 in their hematopoietic system. We demonstrate that both megakaryocytes and platelets possess a functional apoptotic caspase cascade downstream of Bcl-2 family-mediated mitochondrial damage. Caspase-9 is the initiator caspase, and its loss blocks effector caspase activation. Surprisingly, steady-state thrombopoiesis is unperturbed in the absence of caspase-9, indicating that the apoptotic caspase cascade is not required for platelet production. In platelets, loss of caspase-9 confers resistance to the BH3 mimetic ABT-737, blocking phosphatidylserine (PS) exposure and delaying ABT-737a??induced thrombocytopenia in vivo. Despite this, steady-state platelet lifespan is normal. Casp9a??/a?? platelets are fully capable of physiologic hemostatic responses and functional regulation of adhesive integrins in response to agonist. These studies demonstrate that the apoptotic caspase cascade is required for the efficient death of megakaryocytes and platelets, but is dispensable for their generation and function.

UR - http://bloodjournal.hematologylibrary.org/content/119/18/4283.full.pdf

U2 - 10.1182/blood-2011-11-394858

DO - 10.1182/blood-2011-11-394858

M3 - Article

VL - 119

SP - 4283

EP - 4290

JO - Blood

JF - Blood

SN - 0006-4971

IS - 18

M1 - 18

ER -

White MJ, Schoenwaelder SM, Josefsson EC, Jarman KE, Henley KJ, James C et al. Caspase-9 mediates the apoptotic death of megakaryocytes and platelets, but is dispensable for their generation and function. Blood. 2012 May 3;119(18):4283-4290. 18. https://doi.org/10.1182/blood-2011-11-394858