Abstract
Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine cocktails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.
| Original language | English |
|---|---|
| Pages (from-to) | 1505-1513 |
| Number of pages | 9 |
| Journal | Cancer Research |
| Volume | 65 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Feb 15 2005 |
Fingerprint
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells. / De Felice, Lidia; Tatarelli, Caterina; Mascolo, Maria Grazia; Gregorj, Chiara; Agostini, Francesca; Fiorini, Roberto; Gelmetti, Vania; Pascale, Simona; Padula, Fabrizio; Petrucci, Maria Teresa; Arcese, William; Nervi, Clara.
In: Cancer Research, Vol. 65, No. 4, 15.02.2005, p. 1505-1513.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells
AU - De Felice, Lidia
AU - Tatarelli, Caterina
AU - Mascolo, Maria Grazia
AU - Gregorj, Chiara
AU - Agostini, Francesca
AU - Fiorini, Roberto
AU - Gelmetti, Vania
AU - Pascale, Simona
AU - Padula, Fabrizio
AU - Petrucci, Maria Teresa
AU - Arcese, William
AU - Nervi, Clara
PY - 2005/2/15
Y1 - 2005/2/15
N2 - Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine cocktails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.
AB - Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine cocktails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.
UR - http://www.scopus.com/inward/record.url?scp=13944263926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13944263926&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-04-3063
DO - 10.1158/0008-5472.CAN-04-3063
M3 - Article
VL - 65
SP - 1505
EP - 1513
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 4
ER -