Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration

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Abstract

Anti-cancer chemotherapy drugs challenge hematopoietic tissues to regenerate, but commonly produce long-term sequelae. Deficits in hematopoietic stem or stromal cell function have been described, but the mechanisms mediating chemotherapy-induced hematopoietic dysfunction remain unclear. Administration of multiple cycles of cisplatin chemotherapy causes significant sensory neuropathy. Here, we demonstrate that chemotherapy-induced nerve injury in the bone marrow is a critical lesion impairing hematopoietic regeneration. We show using various pharmacological and genetic models that the selective loss of adrenergic innervation in the BM alters its regeneration following genotoxic insult. Sympathetic nerves in the marrow promote the survival of stem cell niche constituents that initiate recovery. Neuroprotection by deletion of Trp53 in sympathetic neurons or neuro-regeneration using 4-methylcatechol or glial-derived neurotrophic factor (GDNF) administration can restore hematopoietic recovery. Thus, these results shed light on the potential benefit of adrenergic nerve protection to shield hematopoietic niches from injury.

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Thorsten Buch, Frank Heppner, Christine Tertilt … (2005)

A new system for lineage ablation is based on transgenic expression of a diphtheria toxin receptor (DTR) in mouse cells and application of diphtheria toxin (DT). To streamline this approach, we generated Cre-inducible DTR transgenic mice (iDTR) in which Cre-mediated excision of a STOP cassette renders cells sensitive to DT. We tested the iDTR strain by crossing to the T cell- and B cell-specific CD4-Cre and CD19-Cre strains, respectively, and observed efficient ablation of T and B cells after exposure to DT. In MOGi-Cre/iDTR double transgenic mice expressing Cre recombinase in oligodendrocytes, we observed myelin loss after intraperitoneal DT injections. Thus, DT crosses the blood-brain barrier and promotes cell ablation in the central nervous system. Notably, we show that the developing DT-specific antibody response is weak and not neutralizing, and thus does not impede the efficacy of DT. Our results validate the use of iDTR mice as a tool for cell ablation in vivo.

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Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche

Andrew Chow, Daniel Lucas, Andrés Hidalgo … (2011)

Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC niche. We defined three populations of BM mononuclear phagocytes that include Gr-1hi monocytes (MOs), Gr-1lo MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin+ niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169+ MΦ, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MΦ depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MΦ cross talk with the Nestin+ niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM MΦ hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.

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The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche.

Yoshiki Omatsu, Tatsuki Sugiyama, Hiroshi Kohara … (2010)

Hematopoietic stem cells (HSCs) and their lympho-hematopoietic progeny are supported by microenvironmental niches within bone marrow; however, the identity, nature, and function of these niches remain unclear. Short-term ablation of CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells in vivo did not affect the candidate niches, bone-lining osteoblasts, or endothelial cells but severely impaired the adipogenic and osteogenic differentiation potential of marrow cells and production of the cytokines SCF and CXCL12 and led to a marked reduction in cycling lymphoid and erythroid progenitors. HSCs from CAR cell-depleted mice were reduced in number and cell size, were more quiescent, and had increased expression of early myeloid selector genes, similar to the phenotype of wild-type HSCs cultured without a niche. Thus, the niche composed of adipo-osteogenic progenitors is required for proliferation of HSCs and lymphoid and erythroid progenitors, as well as maintenance of HSCs in an undifferentiated state. Copyright © 2010 Elsevier Inc. All rights reserved.