Research conducted at The Ohio State University Wexner Medical Center and The Ohio State University College of Medicine found that spinal cord injuries in mice cause an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.
“We also found that it’s possible to overcome certain aspects of spinal cord injury-induced bone marrow failure. This could have an immediate impact on people affected by spinal cord injury,” said lead author Phillip Popovich, chair of the Ohio State Department of Neuroscience and executive director of Ohio State’s Belford Center for Spinal Cord Injury and Center for Brain and Spinal Cord Repair.
Findings are published online in the journal Nature Communications.
Spinal cord injury (SCI) is known to cause immune system dysfunction, which increases the risk of infections. This, in turn, increases hospitalizations and premature death.
Immune cells are made in the bone marrow. Healthy bone marrow requires proper communication with the nervous system, notably the spinal cord.
“Our research shows that spinal cord injury causes stem cells in the bone marrow – those required to make new immune cells – to rapidly divide. But after cell division, these cells become trapped in the bone marrow.
We discovered one possible explanation for this,” said Randall S. Carpenter, first author and recently graduated PhD student from Ohio State’s Neuroscience Graduate program.
Notably, in bone marrow of mice with spinal cord injuries, there’s an increase in chemical signaling between stem progenitor cells and support cells in the bone marrow.
This enhanced signaling locks the cells down so they can’t move away from the “niches” in which they are born and develop.
This lockdown can be reversed by post-injury injections of the FDA-approved drug Plerixafor, a small molecule inhibitor of CXCR4, a chemokine receptor.
Even though Plerixafor frees blood stem cells and mature immune cells from bone marrow, other techniques showed that the intrinsic long-term functional capacity of bone marrow stem/progenitor cells is still impaired for several months post-injury.
Bone marrow failure diseases develop when the bone marrow can’t produce enough healthy mature white and red blood cells.
Normal aging and various diseases including diabetes, cancers and chemotherapy also trap mature and immature cells in the bone marrow.
“In spinal cord injury patients, Plerixafor could be a potentially safe and effective way to mobilize cells from the bone marrow niche to help restore immune function.
In fact, Plerixafor is already used in other clinical indications to help reverse immunodeficiency in patients; it just hasn’t been used after spinal cord injury,” Popovich said.
“While this study was done in mice, these new data help explain observations that have been made in humans with spinal cord injuries,” Popovich said. “More research is needed to understand why the bone marrow failure develops, and whether it’s permanent.”
Patients with an inherited bone marrow failure syndrome (IBMFS) face a variety of complications involving many systems; hematopoietic stem cell transplantation (SCT) may cure some problems, prevent others, and introduce new ones.
The most frequent of these rare genetic syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond Blackfan anemia (DBA), and Shwachman Diamond syndrome (SDS).
The respective pathologic pathways involve DNA repair (FA), telomere biology (DC), and ribosome biogenesis (DBA and SDS).1,2
Many patients present with hematologic findings, such as single-cell or pancytopenia, myelodysplastic syndrome (MDS), or leukemia, particularly acute myeloid leukemia (AML).
The diagnosis of an IBMFS may be revealed during evaluation for the hematologic manifestations, due to observation of specific clinical phenotypes or use of syndrome-specific screening tests or genomic studies.3,4
The syndrome-specific tests are as follows: for FA, increased chromosome breakage in lymphocytes cultured with a DNA cross-linker; for DC, short telomeres by lymphocyte flow cytometry and fluorescent in situ hybridization; for DBA, elevated red cell adenosine deaminase; and for SDS, low levels of serum trypsinogen and isoamylase.5-8
Patients with an IBMFS are usually diagnosed and followed by pediatric hematologists, although we now realize that some patients are identified as adults. Features that lead to diagnosis in childhood, even without hematologic manifestations, include a multitude of syndrome-specific congenital anomalies, as well as complications that may develop with age (Table 1).
The majority of the patients present with or develop cytopenias or hematologic malignancies, and thus the option of SCT is very attractive. Although SCT may cure the bone marrow problem, it may introduce new and, until recently, unanticipated outcomes.
It is important to distinguish an SCT-related late effect from a feature of aging in a person with an IBMFS, which might be independent of the SCT, to offer appropriate counseling, surveillance, and treatment.9,10
Table 1 – Systems involved in patients with an IBMFS
|Hematology||Aplastic anemia, MDS, AML||Aplastic anemia, MDS, AML, lymphomas||Anemia, MDS, AML||Neutropenia, aplastic anemia, MDS, AML|
|Oncology||Head and neck SCC (tongue), vulvar SCC, esophagus, brain, skin||Head and neck SCC (tongue), anogenital SCC, stomach, lung, esophagus, skin||Colon, lung, osteosarcoma, gynecologic, stomach||Ovarian cancer|
|Perinatal||Low birth weight, intrauterine growth retardation||Low birth weight, intrauterine growth retardation||Low birth weight, hydrops||Low birth weight|
|Skin||Café au lait spots, basal cell, and SCC||Lacy reticulated pigmentation, dystrophic nails (soft, brittle, ridged, disappearing), adermatoglyphia, hyperhidrosis, basal cell, and SCCs||—||Ichthyosis, eczema|
|Skeletal||Absent or abnormal thumbs, absent or hypoplastic radius; flat thenar eminence; Klippel Feil, congenital hip dislocation||Avascular necrosis hips or shoulders, osteoporosis, scoliosis, spontaneous fractures||Thumbs triphalangeal, bifid, duplicated, subluxed, extra, hypoplastic; web neck, Sprengel, Klippel-Feil, short neck; scoliosis||Metaphyseal dysostosis; small thorax, narrow chest, pectus carinatum; dysplastic hips, bow legs, short legs, Legg Calve Perthes; short neck; scoliosis; flared ribs; osteopenia|
|Eyes||Microphthalmia, microcornea, ptosis, epicanthal folds, strabismus, cataracts||Epiphora (from lacrimal duct stenosis), blepharitis, exudative retinopathy, retinal neovascularization, retinal hemorrhages, entropion, ectropion, cataracts||Small, epicanthal folds, hypertelorism, hypotelorism, strabismus, cataract, glaucoma||Hypertelorism, retinitis pigmentosum, esotropia|
|Kidney||Ectopic, horseshoe, absent, small, hydronephrosis, hydroureter||—||Horseshoe, duplicated, ectopic, absent||—|
|Gonads, male||Small testes, infertility, undescended, micropenis||Urethral stricture, phimosis, small testes, undescended testes, meatal stenosis, hypospadias||Undescended testes, hypospadias, inguinal hernia||Atrophic testes, hypospadias|
|Gonads, female||Small ovaries, bicornuate uterus, late menarche, early menopause, premature ovarian failure, vulvar cancer, breast cancer||Hymenal and urethral stricture||—||—|
|Pregnancies||Decreased blood counts, fetal loss, pre-eclampsia, failure of labor to progress, cesarean sections, small babies||No apparent problems||Worsening of anemia, fetal loss, pre-eclampsia, intrauterine growth retardation, preterm deliveries, fetal malformations, placental infarcts||—|
|Development||Developmental delay, retardation||Developmental delay, retardation||Developmental delay, retardation||Developmental delay, neurocognitive deficits, attention deficit|
|Otology||Abnormal pinna, narrow canal, conductive or sensory hearing loss||Deaf rare||Low set, small, deaf||Decreased hearing|
|Cardiology||Congenital heart disease, iron overload||Hyperlipidemia||Congenital heart disease, iron overload||Congenital heart disease|
|Endocrine||Short, diabetes, metabolic syndrome, growth hormone deficiency, osteoporosis, hypothyroid, delayed bone age||Short, bone problems (see skeletal), hypogonadism, elevated cholesterol (on androgens)||Short||Short|
|Gastroenterology||Imperforate anus, TE fistula, esophageal/duodenal atresia, annular pancreas, gastric emptying delay, poor weight gain, poor feeding, esophageal SCC||Esophageal stenosis, telangiectasias, varices, ulcers, enteropathy (small bowel), enterocolitis (colon), rectal adenocarcinoma||Stomach and colon cancer||Malabsorption due to exocrine pancreatic insufficiency; diarrhea; inguinal hernia|
|Liver||Cirrhosis, fibrosis, elevated enzymes, iron overload, androgen toxicity, adenoma, hepatocellular carcinoma, peliosis hepatis||Cirrhosis, fibrosis, hepatocellular carcinoma, hepatopulmonary syndrome, portal hypertension, iron overload||Iron overload, hepatocellular carcinoma||Rare hepatomegaly|
|Head||Microcephaly||Microcephaly||Microcephaly, hydrocephalus; cleft palate, cleft lip||Microcephaly, macrocephaly, hydrocephaly; cleft palate, cleft lip|
|Brain||Pituitary stalk interruption, small pituitary, hypopituitarism, absent corpus callosum, cerebellar hypoplasia||Cerebellar hypoplasia, intracranial calcifications||Hypopituitary, Chiari, myelomeningocele||Chiari, cerebellar tonsillar ectopia, hypopituitarism|
|Dental||Poor hygiene, abnormal tooth development, oral ulcers, gum infections, oral SCC||Caries, tooth loss, periodontitis, taurodontism (enlarged pulp chamber), decreased root/crown ratio, leukoplakia, tongue cancer, lichen planus||—||Caries, oral ulcers|
|ENT||Head and neck SCC (oral, pharyngeal, hypopharyngeal, laryngeal)||Head and neck SCC||—||—|
|Immunology||Decreased immunoglobulins, some lymphocyte deficiencies with age||Immunodeficiency of immunoglobulins or lymphopenia in younger children||Essentially normal||Some B- and T-cell deficiencies|
|Lung||—||Pulmonary fibrosis, pulmonary arteriovenous malformations||—||—|
|Hair||—||Early gray, early hair loss, sparse eyebrows and eyelashes||—||—|
|Vascular complications||—||Telangiectases and arteriovenous malformations (retinal, GI, pulmonary)||—||—|
|Psychiatry||Some psychiatric problems|
|Diagnostic screening test||Increased chromosome breakage with DEB or MMC||Decreased telomere length by flow FISH||Increased red cell adenosine deaminase||Decreased pancreatic enzymes (trypsinogen, isoamylase)|
DEB, diepoxybutane; ENT, ear, nose, throat; FISH, fluorescence in situ hybridization; GI, gastrointestinal; MMC, mitomycin C; TE, tracheoesophageal.
Patients with an IBMFS share many age-related complications, independent of the use of SCT, as well as many adverse events that may be exacerbated by SCT. One major concern is iron overload in transfused patients, which is paramount in those with DBA but also may be relevant in any of the others who received substantial red cell support without adequate iron chelation.
Osteopenia or osteoporosis may be increased in patients who were treated with corticosteroids (eg, DBA), although they appear to be unrelated to steroids in FA, DC, and SDS.
Cataracts, ophthalmic and renal complications from chelating agents, hypothyroidism, liver disease, dental caries, progressive immunodeficiency, and problems due to delayed intellectual development may occur in some patients with any of the syndromes.
Finally, increased rates of malignancies are a major concern in all of the IBMFS patients as they age, although the actual types and risks are syndrome specific.
Patients with an IBMFS have some common post-SCT late effects; many of these may be seen in patients receiving transplants for reasons other than an IBMFS, but they may be more frequent or more complicated in those with an IBMFS.10
These may include acute or chronic graft-versus-host disease (GVHD), delayed immune reconstitution, iron overload, pulmonary complications, infertility, renal functional impairment, short stature (from the syndrome, corticosteroids, growth hormone deficiency, or other factors), and psychosocial difficulties of the combination of a syndrome as well as a transplant.
In addition, the potential of the preparative regimen, the transplant, or post-SCT medication increasing the already high risk of malignancy, cannot be neglected. Despite the common features, the major rare syndromes are also very different in their manifestations and complications and are discussed separately below.
Other syndromes are not discussed here because there is insufficient information about transplant-related late effects. The focus of this review is on the syndrome-specific complications associated with growing older and the distinction between the aging-associated developments and those that may be specific to or made worse by transplant.
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