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Stem Cell Niche-Radiobiological Response

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Biology in Stem Cell Niche

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

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Abstract

Ionizing radiation (IR) in the context of radiotherapy or unplanned exposure events results in a myriad of biological events with clinical outcomes that range in severity from DNA damage, local tissue damage, and even death. Radiation is widely utilized in medicine for imaging diagnostics, total body irradiation (TBI) in bone marrow (BM) transplantation and cancer therapy, and for the management of non-cancerous syndromes, including Dupuyten and Ledderhose disease (Halperin in Lancet Oncol 7(8):676–85, 2006; Seegenschmiedt and Attassi in Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al] 179(12):847–853, 2003; Heyd et al. in Organ der Deutschen Rontgengesellschaft [et al] 186(1):24–29, 2010). To eradicate tumors, x-rays, gamma rays, or high-energy charged particle beams are emitted at malignant cells to induce DNA damage and death. The disadvantages associated with radiation therapy include damage to proximal healthy tissues and cell death. The blood forming system is highly sensitive to radiation with increasing risk of morbidity and mortality resulting from loss of white blood cells and platelets with the sequela of opportunistic infection and hemorrhage with increasing duration and intensity of exposure. Radiation therapy increases the risk of infertility, can cause joint and mouth (stoma) complications, and can result in lymphedema and cancer. Irradiation impairs osteogenesis causing cell cycle arrest, reduction of osteoblast proliferation and differentiation (although not initially), collagen and vascular suppression, increased sensitivity to apoptotic agents, osteoradionecrosis, bone demineralization, loss of trabecular connections, sclerosis, and destruction of a stem cell niche that contributes to maintenance of hematopoiesis [Hopewell in Med Pediatr Oncol 41(3):208–211, 2003). In this chapter, we will review what is known regarding the impact of radiation exposure on BM stromal cells that constitute microenvironments/niches that support blood cell production and an overview of hematopoietic stem cell (HSC) radioprotection and regeneration of the stem cell niche. We will outline the acute and late effects of irradiation on hematopoietic stem and progenitor cells leading to hematopoietic acute radiation syndrome (H-ARS) and residual bone marrow damage (RBMD), respectively. The interactive components of the stem cell niche respond to radiation distinctively by cell type and even by state of maturation, and influence the fate of one another. The reader will appreciate a greater understanding of the HSC niche, the radiobiological response as an interconnected symphony, and the therapeutic approach of HSC niche protection and regeneration.

David J. Olivos III and Rajendran Sellamuthu: Contributed equally to this work.

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Abbreviations

α-SMA:

α-smooth muscle actin

Akt:

Serine/threonine-protein kinase

ALP:

Alkaline phosphatase

Ang1:

Angiopoietin-1

ARE:

Anti-oxidant response element

Bak:

BCL-2-antagonist/killer 1

Bax:

BCL-2-like protein 4

bFGF:

Basic fibroblast growth factor

BFU-E:

Burst forming unit-erythroid

BM:

Bone marrow

CAR:

CXCL12-abundant reticular cells

CD:

Cluster of differentiation

CFU-E:

Colony forming unit-erythroid

CFU-F:

Colony-forming unit-fibroblast

CFU-GEMM:

Colony forming unit of granulocytes, erythrocytes, monocyte/macrophages, and megakaryocytes

CFU-GM:

Colony forming units of granulocytes and monocyte

c-Kit:

Cellular receptor-type tyrosine kinase

COX2:

Cyclooxygenase-2

CXCL12:

Chemokine (C-X-C motif) ligand 12

CXCR4:

C-X-C chemokine receptor type 4

DEARE:

Delayed effects of acute radiation exposure

DNA:

Deoxyribonucleic acid

DSB:

Double strand break

EPCs:

Endothelial progenitor cells

FGF:

Fibroblast growth factor

G-CSF:

Granulocyte colony-stimulating factor

GM-CSF:

Granulocyte-macrophage CSF

GSR:

Gluthathione reductase

Gy:

Gray

H-ARS:

Hematopoietic acute radiation syndrome

hFOB:

Human immortalized osteoblast

HO1:

Heme oxygenase-1

HPC:

Hematopoietic progenitor cell

HSC:

Hematopoietic stem cell

HSPC:

Hematopoietic stem progenitor cell

IGF-1:

Insulin-like growth factor-1

IL-6:

Interleukin-6

IR:

Ionizing radiation

KSL:

c-Kit + Sca-1 + Lin-

LD:

Lethal Dose

Lin-:

Lineage-negative

M-CSF:

Macrophage colony stimulating factor

MSC:

Mesenchymal stem cell

mTOR:

Mammalian target of rapamycin

NFκβ:

Nuclear factor kappa β

NK:

Natural killer cell

Nrf2:

Nuclear factor erythroid-2–related factor 2

Notch-IC:

Notch intercellular domain

OPG:

Osteoprotegerin

PDGF:

Platelet derived growth factor

PGE2 :

Prostaglandin E2

PI3K:

Phosphatidylinositol 3-kinase

PK:

Protein kinase

PRR:

Pattern recognition receptor

RANKL:

Receptor activator of nuclear kappa-B ligand

RBC:

Red blood cell

RBMD:

Residual bone marrow damage

RBP-Jk:

Recombination signal binding protein for immunoglobulin kappa J

REDD1:

Regulated in development and DNA damage response 1

ROS:

Reactive oxygen species

Runx2:

Runt-related transcription factor 2

Sca-1:

Stem cell antigen-1 positive

SCF:

Stem cell factor

SDF-1:

Stromal cell-derived factor 1

SSB:

Single strand break

TBI:

Total body irradiation

Tie2:

Tunica internal endothelial cell kinase 2

TLR:

Toll like receptor

TMC:

Trifluoromethyl-2’-methocychalone

TPO:

Thrombopoietin

TRAP:

Tartrate-resistant acid phosphatase

TXNRD1:

Thiordoxin reductase 1

VCAM-1:

Vascular cell adhesion molecule-1

VE-Cadherin:

Vascular endothelial-cadherin

VEGF:

Vascular endothelial growth factor

VEGFR2:

Vascular endothelial growth factor 2

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Acknowledgments

This work was supported in part by NIA R01AG046246 (LMP, MAK, CMO), NIAMS AR060332 (MAK), HL096305 (LMP), NIAID 1U01AI107340 (CMO), NIAID HSN266200500043C (CMO), and NIAID HHSN272201000046C (CMO), the Indiana Center for Excellence in Molecular Hematology (NIDDK P30 DK090948), and a postdoctoral NIH T32 Training Grant in Hematopoiesis, T32 4689736 (DJO). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    David J. Olivos III & Pratibha Singh

  2. Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA

    David J. Olivos III

  3. Indiana University School of Medicine, Indianapolis, IN, USA

    Rajendran Sellamuthu & Sasidhar Vemula

  4. Department of Medicine, Indiana University School of Medicine, 980 W. Walnut St., R3-C341, Indianapolis, IN, 46202, USA

    Louis M. Pelus

  5. Department of Orthopaedic Surgery, Indiana University School of Medicine, 1130 West Michigan St., FH 115, Indianapolis, IN, 46202, USA

    Christie M. Orschell

  6. Department of Microbiology and Immunology, Indiana University School of Medicine, 980 W. Walnut St., R2 327, Indianapolis, IN, 46202, USA

    Melissa A. Kacena

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  1. David J. Olivos III
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Correspondence to Melissa A. Kacena .

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  1. Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    Kursad Turksen

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Olivos III, D.J. et al. (2015). Stem Cell Niche-Radiobiological Response. In: Turksen, K. (eds) Biology in Stem Cell Niche. Stem Cell Biology and Regenerative Medicine. Springer, Cham. https://doi.org/10.1007/978-3-319-21702-4_5

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