Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment

Tony Peled; Hadas Shoham; Dorit Aschengrau; Dima Yackoubov; Gabi Frei; Noga Rosenheimer G; Batya Lerrer; Haim Y. Cohen; Arnon Nagler; Eitan Fibach; Amnon Peled

doi:10.1016/j.exphem.2011.12.005

Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment

Tony Peled
, Hadas Shoham
, Dorit Aschengrau
, Dima Yackoubov
, Gabi Frei
, Noga Rosenheimer G
, Batya Lerrer
, Haim Y. Cohen
, Arnon Nagler
, Eitan Fibach
, Amnon Peled

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

Gamida Cell Ltd. Cell Therapy Technologies
Sheba Medical Center at Tel Hashomer
Hadassah University Medical Centre

Research output: Contribution to journal › Article › peer-review

178 Scopus citations

Abstract

Strategies that increase homing to the bone marrow and engraftment efficacy of ex vivo expended CD34⁺ cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34⁺ cells cultured with cytokines. In the presence of NAM, the fraction of CD34⁺CD38^- cells increased and the fraction of differentiated cells (CD14⁺, CD11b⁺, and CD11c⁺) decreased. CD34⁺ cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD⁺-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34⁺ cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the clinical utility of NAM for ex vivo expansion of functional CD34⁺ cells.

Original language	English
Pages (from-to)	342-355.e1
Journal	Experimental Hematology
Volume	40
Issue number	4
DOIs	https://doi.org/10.1016/j.exphem.2011.12.005
State	Published - Apr 2012

Bibliographical note

We thank Dr. Nadir Askenasy of the Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center of Israel for the critical reading of the manuscript and Mary Clausen, Ido D. Weiss, Katia Beider the Gene Therapy Institute, Hadassah University Hospital, Jerusalem, Israel for technical assistance.

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10.1016/j.exphem.2011.12.005

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Peled, T., Shoham, H., Aschengrau, D., Yackoubov, D., Frei, G., Rosenheimer G, N., Lerrer, B., Cohen, H. Y., Nagler, A., Fibach, E., & Peled, A. (2012). Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Experimental Hematology, 40(4), 342-355.e1. https://doi.org/10.1016/j.exphem.2011.12.005

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title = "Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment",

abstract = "Strategies that increase homing to the bone marrow and engraftment efficacy of ex vivo expended CD34+ cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34+ cells cultured with cytokines. In the presence of NAM, the fraction of CD34+CD38- cells increased and the fraction of differentiated cells (CD14+, CD11b+, and CD11c+) decreased. CD34+ cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD+-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34+ cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the clinical utility of NAM for ex vivo expansion of functional CD34+ cells.",

author = "Tony Peled and Hadas Shoham and Dorit Aschengrau and Dima Yackoubov and Gabi Frei and \{Rosenheimer G\}, Noga and Batya Lerrer and Cohen, \{Haim Y.\} and Arnon Nagler and Eitan Fibach and Amnon Peled",

note = "We thank Dr. Nadir Askenasy of the Department of Pediatric Hematology-Oncology, Schneider Children{\textquoteright}s Medical Center of Israel for the critical reading of the manuscript and Mary Clausen, Ido D. Weiss, Katia Beider the Gene Therapy Institute, Hadassah University Hospital, Jerusalem, Israel for technical assistance.",

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Peled, T, Shoham, H, Aschengrau, D, Yackoubov, D, Frei, G, Rosenheimer G, N, Lerrer, B, Cohen, HY, Nagler, A, Fibach, E & Peled, A 2012, 'Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment', Experimental Hematology, vol. 40, no. 4, pp. 342-355.e1. https://doi.org/10.1016/j.exphem.2011.12.005

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T1 - Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment

AU - Peled, Tony

AU - Shoham, Hadas

AU - Aschengrau, Dorit

AU - Yackoubov, Dima

AU - Frei, Gabi

AU - Rosenheimer G, Noga

AU - Lerrer, Batya

AU - Cohen, Haim Y.

AU - Nagler, Arnon

AU - Fibach, Eitan

AU - Peled, Amnon

N1 - We thank Dr. Nadir Askenasy of the Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center of Israel for the critical reading of the manuscript and Mary Clausen, Ido D. Weiss, Katia Beider the Gene Therapy Institute, Hadassah University Hospital, Jerusalem, Israel for technical assistance.

PY - 2012/4

Y1 - 2012/4

N2 - Strategies that increase homing to the bone marrow and engraftment efficacy of ex vivo expended CD34+ cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34+ cells cultured with cytokines. In the presence of NAM, the fraction of CD34+CD38- cells increased and the fraction of differentiated cells (CD14+, CD11b+, and CD11c+) decreased. CD34+ cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD+-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34+ cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the clinical utility of NAM for ex vivo expansion of functional CD34+ cells.

AB - Strategies that increase homing to the bone marrow and engraftment efficacy of ex vivo expended CD34+ cells are expected to enhance their clinical utility. Here we report that nicotinamide (NAM), a form of vitamin B-3, delayed differentiation and increased engraftment efficacy of cord blood-derived human CD34+ cells cultured with cytokines. In the presence of NAM, the fraction of CD34+CD38- cells increased and the fraction of differentiated cells (CD14+, CD11b+, and CD11c+) decreased. CD34+ cells cultured with NAM displayed increased migration toward stromal cell derived factor-1 and homed to the bone marrow with higher efficacy, thus contributing to their increased engraftment efficacy, which was maintained in competitive transplants with noncultured competitor cells. NAM is a known potent inhibitor of several classes of ribosylase enzymes that require NAD for their activity, as well as sirtuin (SIRT1), class III NAD+-dependent-histone-deacetylase. We demonstrated that EX-527, a specific inhibitor of SIRT1 catalytic activity, inhibited differentiation of CD34+ cells similar to NAM, while specific inhibitors of NAD-ribosylase enzymes did not inhibit differentiation, suggesting that the NAM effect is SIRT1-specific. Our findings suggest a critical function of SIRT1 in the regulation of hematopoietic stem cell activity and imply the clinical utility of NAM for ex vivo expansion of functional CD34+ cells.

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AN - SCOPUS:84858339102

SN - 0301-472X

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SP - 342-355.e1

JO - Experimental Hematology

JF - Experimental Hematology

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ER -

Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment

Abstract

Bibliographical note

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