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1.
Blood ; 120(2): 303-13, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22596259

RESUMO

Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment. Controversy exists on N-cadherin's role in support of HSCs. Specifically, it is unknown whether microenvironmental N-cadherin is required for normal marrow microarchitecture and for hematopoiesis. To determine whether osteoblastic N-cadherin is required for HSC regulation, we used a genetic murine model in which deletion of Cdh2, the gene encoding N-cadherin, has been targeted to cells of the osteoblastic lineage. Targeted deletion of N-cadherin resulted in an age-dependent bone phenotype, ultimately characterized by decreased mineralized bone, but no difference in steady-state HSC numbers or function at any time tested, and normal recovery from myeloablative injury. Intermittent parathyroid hormone (PTH) treatment is well established as anabolic to bone and to increase marrow HSCs through microenvironmental interactions. Lack of osteoblastic N-cadherin did not block the bone anabolic or the HSC effects of PTH treatment. This report demonstrates that osteoblastic N-cadherin is not required for regulation of steady-state hematopoiesis, HSC response to myeloablation, or for rapid expansion of HSCs through intermittent treatment with PTH.


Assuntos
Caderinas/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Osteoblastos/citologia , Osteoblastos/fisiologia , Envelhecimento/genética , Envelhecimento/patologia , Animais , Sequência de Bases , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Densidade Óssea/fisiologia , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/genética , Remodelação Óssea/fisiologia , Osso e Ossos/anatomia & histologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Caderinas/deficiência , Caderinas/genética , Microambiente Celular/fisiologia , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteoblastos/efeitos dos fármacos , Hormônio Paratireóideo/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
2.
Blood ; 119(11): 2489-99, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22262765

RESUMO

Microenvironmental expansion of hematopoietic stem cells (HSCs) is induced by treatment with parathyroid hormone (PTH) or activation of the PTH receptor (PTH1R) in osteoblastic cells; however, the osteoblastic subset mediating this action of PTH is unknown. Osteocytes are terminally differentiated osteoblasts embedded in mineralized bone matrix but are connected with the BM. Activation of PTH1R in osteocytes increases osteoblastic number and bone mass. To establish whether osteocyte-mediated PTH1R signaling expands HSCs, we studied mice expressing a constitutively active PTH1R in osteocytes (TG mice). Osteoblasts, osteoclasts, and trabecular bone were increased in TG mice without changes in BM phenotypic HSCs or HSC function. TG mice had progressively increased trabecular bone but decreased HSC function. In severely affected TG mice, phenotypic HSCs were decreased in the BM but increased in the spleen. TG osteocytes had no increase in signals associated with microenvironmental HSC support, and the spindle-shaped osteoblastic cells that increased with PTH treatment were not present in TG bones. These findings demonstrate that activation of PTH1R signaling in osteocytes does not expand BM HSCs, which are instead decreased in TG mice. Therefore, osteocytes do not mediate the HSC expansion induced by PTH1R signaling. Further, osteoblastic expansion is not sufficient to increase HSCs.


Assuntos
Remodelação Óssea , Células-Tronco Hematopoéticas/citologia , Osteoblastos/citologia , Osteócitos/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/fisiologia , Animais , Citometria de Fluxo , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Transgênicos , Mutação/genética , Osteoblastos/metabolismo , Osteócitos/citologia , Hormônio Paratireóideo/metabolismo , Ratos , Transdução de Sinais
3.
Stem Cells ; 31(2): 372-83, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23169593

RESUMO

Hematopoietic stem and progenitor cells (HSPCs), which continuously maintain all mature blood cells, are regulated within the marrow microenvironment. We previously reported that pharmacologic treatment of naïve mice with prostaglandin E2 (PGE2) expands HSPCs. However, the cellular mechanisms mediating this expansion remain unknown. Here, we demonstrate that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate. In a murine model of sublethal total body irradiation (TBI), in which HSPCs are rapidly lost, treatment with a long-acting PGE2 analog (dmPGE2) reversed the apoptotic program initiated by TBI. dmPGE2 treatment in vivo decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity. The antiapoptotic effect of dmPGE2 on HSPCs did not impair their ability to differentiate in vivo, resulting instead in improved hematopoietic recovery after TBI. dmPGE2 also increased microenvironmental cyclooxygenase-2 expression and expanded the α-smooth muscle actin-expressing subset of marrow macrophages, thus enhancing the bone marrow microenvironmental response to TBI. Therefore, in vivo treatment with PGE2 analogs may be particularly beneficial to HSPCs in the setting of injury by targeting them both directly and also through their niche. The current data provide rationale for in vivo manipulation of the HSPC pool as a strategy to improve recovery after myelosuppression.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Dinoprostona/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Actinas/genética , Actinas/imunologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Células da Medula Óssea/patologia , Células da Medula Óssea/efeitos da radiação , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Microambiente Celular/efeitos dos fármacos , Microambiente Celular/efeitos da radiação , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Dinoprostona/análogos & derivados , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos da radiação , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/efeitos da radiação , Macrófagos/patologia , Macrófagos/efeitos da radiação , Masculino , Camundongos , Camundongos Transgênicos , Lesões Experimentais por Radiação/imunologia , Lesões Experimentais por Radiação/patologia , Irradiação Corporal Total
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