Bone Marrow Failure Syndrome : Spinal cord injuries cause stem cells in the bone marrow to rapidly divide


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

HematologyAplastic anemia, MDS, AMLAplastic anemia, MDS, AML, lymphomasAnemia, MDS, AMLNeutropenia, aplastic anemia, MDS, AML
OncologyHead and neck SCC (tongue), vulvar SCC, esophagus, brain, skinHead and neck SCC (tongue), anogenital SCC, stomach, lung, esophagus, skinColon, lung, osteosarcoma, gynecologic, stomachOvarian cancer
PerinatalLow birth weight, intrauterine growth retardationLow birth weight, intrauterine growth retardationLow birth weight, hydropsLow birth weight
SkinCafé au lait spots, basal cell, and SCCLacy reticulated pigmentation, dystrophic nails (soft, brittle, ridged, disappearing), adermatoglyphia, hyperhidrosis, basal cell, and SCCsIchthyosis, eczema
SkeletalAbsent or abnormal thumbs, absent or hypoplastic radius; flat thenar eminence; Klippel Feil, congenital hip dislocationAvascular necrosis hips or shoulders, osteoporosis, scoliosis, spontaneous fracturesThumbs triphalangeal, bifid, duplicated, subluxed, extra, hypoplastic; web neck, Sprengel, Klippel-Feil, short neck; scoliosisMetaphyseal dysostosis; small thorax, narrow chest, pectus carinatum; dysplastic hips, bow legs, short legs, Legg Calve Perthes; short neck; scoliosis; flared ribs; osteopenia
EyesMicrophthalmia, microcornea, ptosis, epicanthal folds, strabismus, cataractsEpiphora (from lacrimal duct stenosis), blepharitis, exudative retinopathy, retinal neovascularization, retinal hemorrhages, entropion, ectropion, cataractsSmall, epicanthal folds, hypertelorism, hypotelorism, strabismus, cataract, glaucomaHypertelorism, retinitis pigmentosum, esotropia
KidneyEctopic, horseshoe, absent, small, hydronephrosis, hydroureterHorseshoe, duplicated, ectopic, absent
Gonads, maleSmall testes, infertility, undescended, micropenisUrethral stricture, phimosis, small testes, undescended testes, meatal stenosis, hypospadiasUndescended testes, hypospadias, inguinal herniaAtrophic testes, hypospadias
Gonads, femaleSmall ovaries, bicornuate uterus, late menarche, early menopause, premature ovarian failure, vulvar cancer, breast cancerHymenal and urethral stricture
PregnanciesDecreased blood counts, fetal loss, pre-eclampsia, failure of labor to progress, cesarean sections, small babiesNo apparent problemsWorsening of anemia, fetal loss, pre-eclampsia, intrauterine growth retardation, preterm deliveries, fetal malformations, placental infarcts
DevelopmentDevelopmental delay, retardationDevelopmental delay, retardationDevelopmental delay, retardationDevelopmental delay, neurocognitive deficits, attention deficit
OtologyAbnormal pinna, narrow canal, conductive or sensory hearing lossDeaf rareLow set, small, deafDecreased hearing
CardiologyCongenital heart disease, iron overloadHyperlipidemiaCongenital heart disease, iron overloadCongenital heart disease
EndocrineShort, diabetes, metabolic syndrome, growth hormone deficiency, osteoporosis, hypothyroid, delayed bone ageShort, bone problems (see skeletal), hypogonadism, elevated cholesterol (on androgens)ShortShort
GastroenterologyImperforate anus, TE fistula, esophageal/duodenal atresia, annular pancreas, gastric emptying delay, poor weight gain, poor feeding, esophageal SCCEsophageal stenosis, telangiectasias, varices, ulcers, enteropathy (small bowel), enterocolitis (colon), rectal adenocarcinomaStomach and colon cancerMalabsorption due to exocrine pancreatic insufficiency; diarrhea; inguinal hernia
LiverCirrhosis, fibrosis, elevated enzymes, iron overload, androgen toxicity, adenoma, hepatocellular carcinoma, peliosis hepatisCirrhosis, fibrosis, hepatocellular carcinoma, hepatopulmonary syndrome, portal hypertension, iron overloadIron overload, hepatocellular carcinomaRare hepatomegaly
HeadMicrocephalyMicrocephalyMicrocephaly, hydrocephalus; cleft palate, cleft lipMicrocephaly, macrocephaly, hydrocephaly; cleft palate, cleft lip
BrainPituitary stalk interruption, small pituitary, hypopituitarism, absent corpus callosum, cerebellar hypoplasiaCerebellar hypoplasia, intracranial calcificationsHypopituitary, Chiari, myelomeningoceleChiari, cerebellar tonsillar ectopia, hypopituitarism
DentalPoor hygiene, abnormal tooth development, oral ulcers, gum infections, oral SCCCaries, tooth loss, periodontitis, taurodontism (enlarged pulp chamber), decreased root/crown ratio, leukoplakia, tongue cancer, lichen planusCaries, oral ulcers
ENTHead and neck SCC (oral, pharyngeal, hypopharyngeal, laryngeal)Head and neck SCC
ImmunologyDecreased immunoglobulins, some lymphocyte deficiencies with ageImmunodeficiency of immunoglobulins or lymphopenia in younger childrenEssentially normalSome B- and T-cell deficiencies
LungPulmonary fibrosis, pulmonary arteriovenous malformations
HairEarly gray, early hair loss, sparse eyebrows and eyelashes
Vascular complicationsTelangiectases and arteriovenous malformations (retinal, GI, pulmonary)
PsychiatrySome psychiatric problems
Diagnostic screening testIncreased chromosome breakage with DEB or MMCDecreased telomere length by flow FISHIncreased red cell adenosine deaminaseDecreased 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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