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PubMed2005

Pharmacodynamic analysis of changes in reticulocyte subtype distribution in phlebotomy-induced stress erythropoiesis.

Changes in the reticulocyte subtype distribution (high, medium and low reticulocytes count (HR, MR, LR)) measured by flow cytometry following phlebotomy-induced stress erythropoiesis (abruptly dropping hemoglobin to 3-4 g/dl over 4-5 hr) and the pharmacodynamic (PD) relationship to the stimulated erythropoietin (EPO) was investigated in sheep. A PD model was developed that describes the relationship between EPO and the reticulocyte maturity distribution fractions (r=0.95+/-0.02, mean +/- SD). The lag-time between EPO activation of erythroid progenitor cells and the subsequent increase in the least mature HR fraction in the peripheral circulation was 0.72 +/- 0.08 days. The mean transition times (in days) for all three reticulocyte fractions changed at baseline from, T(HR) : 0.09 +/- 0.06, T(MR) : 0.06 +/- 0.04, and T(LR) : 0.46 +/- 0.24 to T(HR) : 0.13 +/- 0.08, T(MR) : 0.29 +/- 0.15, and T(LR) : 2.3 +/- 0.24 under stress erythropoiesis. The total mean residence time for a reticulocyte in the peripheral circulation, T(total) (T(HR) + T(MR) + T(LR)), increased from 0.60 +/- 0.33 days under basal to 2.8 +/- 0.09 days during stress erythropoiesis. The statistically significant increase observed for T(LR) and T(total) supports the hypothesis that stress erythropoiesis perturbs the mean reticulocyte transition times. A correlation analysis between various new, proposed metrics involving the HR, MR and LR fractions and the total reticulocyte count, with the latter indicative of stress erythropoiesis at higher total counts, revealed a highly significant correlation indicating these new metrics may be a valuable adjunct to the reticulocyte maturation index (RMI) and the immature reticulocyte fractions index (IRF) previously used in assessing erythropoietic activity in response to anemia.

Anemia↗

PubMed1988

Changes in heat shock protein synthesis and hsp70 gene transcription during erythropoiesis of Xenopus laevis.

As erythroid cells of Xenopus laevis differentiate, their capacity for transcription and protein synthesis becomes progressively restricted. Mature erythrocytes are thought to be transcriptionally inert and have very low levels of protein synthesis (Maclean et al., 1973, Cell Differ. 2, 261-269). We have examined actual and potential synthetic activity during erythropoiesis by comparing the patterns of protein synthesis and measuring the transcriptional activity of selected genes under ambient and heat shock conditions. As erythropoiesis proceeds, there is a progressive decrease in the number of heat shock proteins (hsps) whose synthesis is induced at elevated temperatures. Despite this repression, mature erythrocytes are able to respond to heat shock with the induction of synthesis of one protein, hsp70. In addition, an hsp70-like protein is synthesized constitutively in orthochromatic erythroblasts, the final erythroid cell stage before maturation into erythrocytes. An in vitro nuclear run-off transcription assay was used to study transcription of the hsp70, beta-globin, and ribosomal genes during erythropoiesis. beta-Globin and ribosomal gene transcription were detected at all stages of erythropoiesis, including the erythrocyte stage. However, transcription of the beta-globin gene relative to ribosomal gene transcription declines substantially in erythrocytes as compared to earlier stages. Hsp70 gene transcription shows both stage-specific and heat shock-dependent transcription. Orthochromatic erythroblasts and erythrocytes have heat shock-dependent hsp70 gene transcription, whereas the gene is transcribed at the earlier erythroblast stages at ambient temperature as well as during heat shock. The constitutive hsp70 transcripts made during these earlier stages may be stored for utilization in constitutive synthesis of the hsp70-like protein in orthochromatic erythroblasts. These data indicate that although erythrocytes become synthetically repressed during differentiation, they are less inert than previously thought. The data also reveal that the synthesis of hsps and related proteins is subject to both transcriptional and post-transcriptional control during erythropoiesis.

Animals↗

PubMed2006

A small-scale serum-free liquid cell culture model of erythropoiesis to assess the effects of exogenous factors.

Anaemia is an important global health problem. Therefore, it is crucial to understand its pathophysiology in various genetic or infectious diseases where dyserythropoiesis is a key pathological feature. To this effect, reproducible and reliable models of erythropoiesis in vitro are much needed as investigative tools. We have developed a serum-free liquid culture model of erythropoiesis using human umbilical cord blood CD34(+) cells cultured in the cytokine combination, interleukin-3 (IL-3), IL-6, stem cell factor (SCF) and erythropoietin (Epo), over 14 days. We found that these culture conditions favored erythroid differentiation over the expansion of the more primitive erythroid precursors. With an initiating culture density of 5x10(4) cells per ml, the nucleated cell fold expansion increased from 7.9+/-3.9 (range 4.5 to 11.1) after 4 days to 2990.2+/-1936.1 (range 626.6 to 6912.0) after 14 days in culture. Day-14 burst-forming unit-erythroid (BFU-E) frequencies peaked at day 4 (24.0+/-8.9%), with a marked decrease in BFU-E burst size as the cultures progressed. Time-course immunophenotypical profiles were characteristically erythroid with a decrease in CD34 expression (from 96.8+/-3.0% at day 0 to 0.8+/-0.8% at day 14), and a concomitant increase in the expression of erythroid-specific markers, CD36, glycophorin A (GpA) and CD71 (from 14.8+/-5.0%, 1.7+/-1.0% and 37.9+/-18.0% to 93.0+/-7.0%, 82.1+/-14.0% and 95.7+/-3.0%, respectively). Morphological studies revealed the presence of normoblasts with the complete absence of reticulocytes and mature erythrocytes after 14 days in culture. Once the culture conditions were optimized, we scaled down our culture model from 24-well plate (large-scale) to 96-well plate cultures (small-scale). We found that the small-scale cultures compared favorably with their large-scale counterpart in terms of erythroid progenitor cell proliferation and differentiation, particularly at low CD34(+) initiating cell doses. By using tumor necrosis factor-alpha (TNF-alpha), a known inhibitor of erythropoiesis, we validated our model system and showed a dose-dependent inhibition of erythroid differentiation with TNF-alpha in our cultures. Therefore, our results demonstrate a small-scale serum-free liquid culture model of erythropoiesis that is comparable with and complements our well-defined large-scale model. Our system would prove useful for screening the effects of exogenous factors on erythropoiesis in vitro.

Cell Culture Techniques↗

PubMed2004

Apoptotic mechanisms in the control of erythropoiesis.

Erythropoiesis is a complex multistep process encompassing the differentiation of hemopoietic stem cells to mature erythrocytes. The steps involved in this complex differentiation process are numerous and involve first the differentiation to early erythoid progenitors (burst-forming units-erythroid, BFU-E), then to late erythroid progenitors (colony-forming units-erythroid) and finally to morphologically recognizable erythroid precursors. A key event of late stages of erythropoiesis is nuclear condensation, followed by extrusion of the nucleus to produce enucleated reticulocytes and finally mature erythrocytes. During the differentiation process, the cells became progressively sensitive to erythropoietin that controls both the survival and proliferation of erythroid cells. A normal homeostasis of the erythropoietic system requires an appropriate balance between the rate of erythroid cell production and red blood cell destruction. Growing evidences outlined in the present review indicate that apoptotic mechanism play a relevant role in the control of erythropoiesis under physiologic and pathologic conditions. Withdrawal of erythropoietin or stimulation of death receptors such as Fas or TRAIL-Rs leads to activation of a subset of caspase-3, -7 and -8, which then cleave the transcription factors GATA-1 and TAL-1 and trigger apoptosis. In addition, there is evidence that a number of caspases are physiologically activated during erythroid differentiation and are functionally required for erythroid maturation. Several caspase substrates are cleaved in differentiating cells, including the protein acinus whose activation by cleavage is required for chromatin condensation. The studies on normal erythropoiesis have clearly indicated that immature erythroid precursors are sensitive to apoptotic triggering mediated by activation of the intrinsic and extrinsic apoptotic pathways. These apoptotic mechanisms are frequently exacerbated in some pathologic conditions, associated with the development of anemia (ie, thalassemias, multiple myeloma, myelodysplasia, aplastic anemia). The considerable progress in our understanding of the apoptotic mechanisms underlying normal and pathologic erythropoiesis may offer the way to improve the treatment of several pathologic conditions associated with the development of anemia.

Anemia↗

PubMed1977

Erythropoiesis in familial erythrocytosis.

We found primary erythrocytosis in two male siblings with hematologically normal parents. To clarify the abnormalities in erythropoiesis, we studied erythropoietin production in the older sibling as well as in vivo and in vitro responses of bone marrow to various stimuli. His erythropoietin excretion after a 1000-ml phlebotomy increased by 0 to 11 units per day. In liquid-suspension culture, erythropoiesis was prominently augmented by erythropoietin and unstimulated erythropoiesis was greater and more prolonged than normal. Numbers of erythroid colonies rose in methylcellulose culture without exogenous erythropoietin, and cloning increased with added erythropoietin. Anti-erythropoietin antibody substantially decreased erythropoiesis in vitro. Increased bone-marrow erythropoiesis was also demonstrated in murine diffusion chambers. The principal abnormality in this familial erythrocytosis appears to be a greatly expanded erythropoietic precursor pool that is responsive to erythropoietin in vitro and in vivo. This abnormality is analogous to the functional erythropoietic defect in typical polycythemia vera.

Adult↗

PubMedDate not supplied

Erythropoiesis associated with viral hepatitis in end stage renal disease.

We describe an end stage renal disease (ESRD) patient on maintenance hemodialysis who developed a spontaneous increase in erythropoiesis associated with an episode of viral hepatitis. Resolution of the hepatitis was accompanied by a reduction in erythropoiesis with the hemoglobin and hematocrit falling back toward the patient's low baseline levels. Plasma erythropoietin (Ep) titers were measured during the period of active erythropoiesis and were found to be low to low normal. The unusual phenomenon of increased erythropoiesis in ESRD following liver injury has been previously described and is thought to be mediated through increased hepatitic Ep production. The low Ep titers measured in our patient, however, suggest that the liver may be capable of stimulating erythropoiesis by another mechanism.

Aged↗

PubMed1981

Erythropoiesis in myelofibrosis with myeloid metaplasia: recognition of different classes of patients by erythrokinetics.

A quantitative assessment of erythropoiesis was performed by means of a mathematical model of iron kinetics in 26 patients with myelofibrosis with myeloid metaplasia (MMM). A direct relationship between total erythropoiesis and red cell volume was revealed. This 'inverse' characteristic of erythropoietic control was the best marker of the proliferative nature of the disease. Three classes of patients were singled out by means of a cluster analysis of the erythrokinetic parameters. In class I (11 patients) the red cell volume was above the predicted normal in all but two patients. Erythropoiesis was sustained at 5--10 times the normal levels with a high degree of ineffective erythropoiesis. A fairly constant absence of erythroid activity over the sacral marrow was demonstrated. In class II most of the 12 patients had a decreased red cell volume. Erythropoiesis was sustained at 2--4 times the normal level with a high degree of peripheral haemolysis. Erythroid activity was recognized over the sacral area in all but two patients. The three patients of class III showed a pattern of erythroid failure and had the worst prognosis. It is suggested that these classes represent separate disease forms of MMM.

Adult↗

PubMed1985

Regulation of erythropoiesis during rapid growth.

High levels of plasma erythropoiesis stimulating factor(s) (ESF) have been found in neonatal WLO-mice during the period of rapid growth. If the high ESF activity is due to the concomitant physiological anaemia of infancy alone, it should be possible to block erythropoiesis by hypertransfusion. Mice were hypertransfused starting on day 14, and killed on day 20. Although hypertransfusion reduced the ESF levels by approximately 55% (P less than 0.001), ESF levels were still detectable in the cell culture assay used (P less than 0.001). Moreover, hypertransfused mice showed active erythropoiesis in the bone marrow, and none had a reticulocyte count below 2%. No correlation was found between PCV and ESF in the hypertransfused animals (r = 0.07, P greater than 0.5), nor was there any difference in weight gain between control and hypertransfused mice (P greater than 0.5). These results show that hypertransfusion did not totally supress erythropoiesis in neonatal WLO-mice, which is different from hypertransfused adult mice. The data indicate that the high plasma ESF found in neonatal WLO-mice during the growth period are not due to the anaemia alone. These findings support studies indicating that regulation of erythropoiesis in the neonate differs from the adult. Factors related to growth per se could be responsible for this difference.

Animals↗

PubMed1986

Quantitative assessment of erythropoiesis in bone marrow expansion areas using 52Fe.

Quantitative 52Fe scans were performed in 180 patients. Expansion of bone marrow was observed in 70. This bone marrow expansion was a nearly constant feature in haemolytic anaemia and in sideroblastic anaemia. It occurred in a third of the patients with myelofibrosis. In patients with polycythaemia rubra vera, expansion was noticed in only two out of seven. Erythropoiesis in expansion areas occurred despite persistence of fat in the iliac crest bone marrow biopsy. It could exist with a slight increase in erythropoiesis and might develop only after a long period of erythropoietic stimulation. Increased marrow activity can take place without erythropoietic expansion in long bones. The fraction of iron uptake in expansion areas did not exceed a third of total marrow iron uptake. With increasing erythropoiesis, the increase in iron uptake in expansion areas was less marked than the increase in the central areas. Erythropoiesis in expansion areas was usually not of major quantitative importance but could nevertheless reach the erythropoiesis of a normal adult.

Adult↗

PubMed1988

In vivo studies on the relationship between intestinal iron (Fe3+) absorption, hypoxia and erythropoiesis in the mouse.

The effect of hypoxia and changes in erythropoiesis on the absorption of 59Fe3+ from in situ tied-off duodenal segments was studied in the mouse. Hypoxia led to an increase in mucosal uptake within 6 h, whilst mucosal transfer was unaffected for about 20 h, suggesting independent regulation of these two processes. Hypoxia (3 d) stimulated erythropoiesis and resulted in a 2-3-fold increase in the total mucosal uptake of 59Fe. Conversely, hyperoxia (100% O2) caused a decrease in reticulocyte counts and the total mucosal uptake. The changes in the transfer of 59Fe from the mucosa to the body were more marked than changes in uptake in both hypoxia and hyperoxia. Mice subjected to subtotal nephrectomy showed a normal increase in the total mucosal uptake of 59Fe3+ following hypoxic exposure, despite the absence of any changes in the reticulocyte count. Obliteration of the erythroid tissue of animals by splenectomy and 89Sr treatment was accompanied by a marked decrease in the transfer of 59Fe from mucosa to the carcass. However, exposure of splenectomized 89Sr-treated mice to hypoxia resulted in an increase in the total mucosal uptake and carcass transfer of 59Fe, without any change in erythropoiesis. These results indicate that hypoxia enhances mucosal iron uptake by a mechanism which is independent of stimulated erythropoiesis, but that changes in the rate of erythropoiesis have an additional effect, particularly on the transfer phase of iron absorption.

Animals↗

PubMed1992

Erythropoiesis in multiple myeloma: defective red cell production due to inappropriate erythropoietin production.

We investigated the pathophysiology of erythropoiesis in 62 patients with multiple myeloma and examined whether it would establish a rational basis for the treatment of their anaemia with recombinant human erythropoietin. Erythropoietin (Epo) production was evaluated by serum levels and erythropoiesis was quantitated by serum transferrin receptor (TfR) levels, both assessed relative to the degree of anaemia. Instead of the expected stimulation of erythropoiesis in response to anaemia, haematocrit correlated positively with marrow erythropoietic activity, indicating that the mechanism of anaemia was primarily defective red cell production. Erythropoiesis decreased and anaemia worsened significantly with advancing clinical stage. 25% of the patients had inadequate Epo production and this proportion increased to 50% in stage 3. Inappropriate Epo production was seen in 60% of patients with renal impairment but was also observed in a number of patients with normal renal function. Erythropoiesis correlated strongly with the adequacy of Epo production, particularly in advanced disease. We conclude that most myeloma patients have defective red cell production even in the absence of massive marrow infiltration and that inappropriate Epo production contributes to their anaemia.

Adult↗

PubMed2005

Erythropoiesis and red cell function in vertebrate embryos.

All vertebrate embryos produce a specific erythroid cell population--primitive erythrocytes--early in development. These cells are characterized by expression of the specific embryonic haemoglobins. Many aspects of primitive erythropoiesis and the physiological function of primitive red cells are still enigmatic. Nevertheless, recent years have seen intensive efforts to characterize in greater detail the molecular events underlying the initiation of erythropoiesis in vertebrate embryos. Several key genes have been identified that are necessary for primitive and the subsequent definitive erythropoiesis, which differs in several aspect from primitive erythropoiesis. This review gives in its first part a short overview dealing with comparative aspects of primitive and early definitive erythropoiesis in higher and lower vertebrates and in the second part we discuss the physiological function of primitive red cells based mainly on results from mammalian and avian embryos.

Amphibians↗

PubMed2005

Functional but abnormal adult erythropoiesis in the absence of the stem cell leukemia gene.

Previous studies have indicated that the stem cell leukemia gene (SCL) is essential for both embryonic and adult erythropoiesis. We have examined erythropoiesis in conditional SCL knockout mice for at least 6 months after loss of SCL function and report that SCL was important but not essential for the generation of mature red blood cells. Although SCL-deleted mice were mildly anemic with increased splenic erythropoiesis, they responded appropriately to endogenous erythropoietin and hemolytic stress, a measure of late erythroid progenitors. However, SCL was more important for the proliferation of early erythroid progenitors because the predominant defects in SCL-deleted erythropoiesis were loss of in vitro growth of the burst-forming erythroid unit and an in vivo growth defect revealed by transplant assays. With respect to erythroid maturation, SCL-deleted proerythroblasts could generate more mature erythroblasts and circulating red blood cells. However, SCL was required for normal expression of TER119, one of the few proposed target genes of SCL. The unexpected finding that SCL-independent erythropoiesis can proceed in the adult suggests that alternate factors can replace the essential functions of SCL and raises the possibility that similar mechanisms also explain the relatively minor defects previously observed in SCL-null hematopoietic stem cells.

Aging↗

PubMed1994

Zinc protoporphyrin and iron-deficient erythropoiesis.

Iron-deficient erythropoiesis may occur in patients with adequate levels of storage iron as well as those with tissue iron deficiency. Here we compare two methods of detecting iron-deficient erythropoiesis. The measurement of percent hypochromic cells in the full blood count provides a direct indicator of iron-deficient erythropoiesis. The zinc protoporphyrin (ZPP) determination is simple, precise and reproducible, and also appears to provide a sensitive index of iron-deficient erythropoiesis. There was a significant correlation between ZPP levels and percent hypochromic cells in patients with iron deficiency anaemia, rheumatoid arthritis and with patients with renal failure undergoing dialysis and receiving erythropoietin. However in the latter group ZPP levels were raised in almost all patients, suggesting that there may be interference by other metabolites in the assay. This may be overcome by washing the red cells before assay, but the procedure becomes cumbersome. If the laboratory is equipped to determine percent hypochromic cells during the blood count this direct measure of iron-deficient erythropoiesis dispenses with the need to determine ZPP. Otherwise ZPP determinations on washed cells may be of diagnostic use.

Anemia, Hypochromic↗

PubMed1993

Variations in erythropoiesis and serum ferritin during erythropoietin therapy for anaemia of end-stage renal disease.

In order to study the relationship between erythropoiesis and serum ferritin (SF) during erythropoietin (rHuEPO) therapy in the anaemia of end-stage renal disease (ESRD), 19 patients were followed without iron supplementation and at a fixed dose of the drug (40 U/kg). Twelve patients failed to attain the target haemoglobin (Hb) value, 7 of whom due to the appearance of iron deficiency. Erythropoiesis, as measured by the serum transferrin receptor concentration, increased from 12 to 120% of the basal value. This increment was not constantly associated with a proportional rise of Hb or reticulocyte count. SF decreased exponentially from a median value of 221 micrograms/dl (range 42-470) to a median value of 54 micrograms/dl (range 20-172). Halving of the basal SF value (SF-T50) was reached at the 18th-95th day of therapy (median = 43), representing a iron shift of 3.4-11.6 mg/day (median = 5.4). SF-T50 was not correlated with the Hb increase, but with that of erythropoiesis (r = 0.78; p = 0.003). The minimum SF (MSF) value attained was not correlated with the appearance of iron deficiency. The conclusion is that the rate of SF decrease during rHuEPO in ESRD is a reliable measure of iron mobilisation for erythropoiesis, but not for haematologic response. The MSF value reached during therapy is not representative of available iron for erythropoiesis.

Adolescent↗

PubMed2026

Angiotensin signaling is essential for stress erythropoiesis but causes retention of dysfunctional mitochondria in RBCs.

We previously reported that excessive angiotensin-II→AT receptor-1 (AT→ATR1) signaling results in sickle cell anemia-associated (SCA-associated) nephropathy. Herein, we showed that hyperangiotensinemia in SCA results from high erythroid cell-generated reactive oxygen species (ROS), which oxidized angiotensinogen (ATGN) and favored its rapid conversion to AT. Increased AT→ATR1 signaling in SCA erythroid cells generated ROS and created a positive feedback loop of ROS→oxidized ATGN→AT→ATR1→ROS, perpetuating the hyperangiotensinemia. ATR1 blocker, losartan, reduced erythrocyte ROS, oxidized ATGN, and AT levels. The ROS→AT→ATR1→ROS loop was driven by sickle erythropoiesis, as it was reproduced when WT mice were transplanted with SCA hematopoiesis. Using SCA and WT mice with germline- and erythroid-specific ATR1 deficiency, we found that stress erythropoiesis, but not steady-state erythropoiesis, was critically dependent on erythroid AT→ATR1 signaling, which acted in harmony with increased erythropoietin signaling. Furthermore, instead of the canonical AT→ATR1→NADPH-oxidase→ROS signaling in steady-state erythropoiesis, AT→ATR1 signaling in stress erythroid cells increased mitochondrial mass and dysfunctional mitochondria, which thereby increased ROS. SCA mice with erythroid-specific ATR1 deficiency had decreased RBC accumulation of dysfunctional mitochondria and decreased ROS, which reduced SCA-associated nephropathy. Overall, we demonstrate that AT→ATR1 signaling was essential for stress erythropoiesis but led to increased dysfunctional mitochondria retention in mature RBCs, which generated ROS and perpetuated hyperangiotensinemia, resulting in end-organ damage.

Animals↗

PubMed1979

Hormonal stimulation of erythropoietin production and erythropoiesis in anephric sheep fetuses.

The effect of testosterone (DT) and thyroxin (L-T4) on erythropoiesis and erythropoietin (Ep) production was studied in control and nephrectomized sheep fetuses beginning at about 100 d of gestation. Fetuses were given injections of either 1.2 mg/d x 13 of L-T4, 12 mg, once every 5 d x 3 of DT or the vehicle alone. Fetal plasma samples for Ep determinations were obtained before and at intervals after the start of the treatment. Reticulocyte and hematocrit levels, and the percent erythrocyte-59Fe uptake values were used to assess erythropoiesis in each fetus. No Ep was detected in plasmas of control fetuses, while significant amounts of Ep were present in plasma obtained from DT- and L-T4-treated intact fetuses. Bilateral nephrectomy did not diminish the Ep response to DT and L-T4. In both intact and nephrectomized fetuses, treatment with DT resulted in the production of significantly greater amounts of Ep than L-T4. The rise in Ep in all groups was accompanied by increases in reticulocytes (2.2 +/- 0.2% vs L-T4:8.1 +/- 0.4% and DT:7.6 +/- 0.7%), percent erythrocyte-59Fe uptake (20.5 +/- 2.9% vs. L-T4:36.7 +/- 3.8% and DT:39.1 +/- 4.0%) and hematocrit (31.2 +/- 2% vs. L-T4:41.8 +/- 3% and DT:48.6 +/- 4.2%). The enhanced erythropoiesis in all groups of nephrectomized fetuses was dependent upon the presence of Ep, because the administration of anti-Ep to these fetuses resulted in the suppression of erythropoiesis in all three groups. These data demonstrate that (a) DT and L-T4 are effective promoters of extrarenal Ep production, thereby enhancing erythropoiesis in intact and nephrectomized fetuses; (b) DT is a stronger stimulus of extrarenal Ep formation than L-T4; and (c) Ep is required for the expression of the erythropoietic effects of L-T4 and DT.

Animals↗

PubMed2005

Evidence for ineffective erythropoiesis in severe sickle cell disease.

Peripheral destruction of sickled erythrocytes is a cardinal feature of sickle cell disease (SCD). Less well established is the potential contribution of ineffective erythropoiesis to the pathophysiology of this hemoglobinopathy. Since patients with SCD frequently develop mixed hematopoietic chimerism after allogeneic nonmyeloablative stem cell transplantation, we used this opportunity to directly compare the differentiation and survival of SCD and donor-derived erythropoiesis in vivo. Donor and recipient erythropoiesis was compared in 4 patients with SCD and 4 without SCD who developed stable mixed hematopoietic chimerism following transplant. Molecular analysis of chimerism in peripheral blood and bone marrow demonstrated higher expression of donor-derived beta-globin RNA relative to the level of donor-derived genomic DNA in patients with SCD. Analysis of chimerism in immature (glycophorin A-positive [GYPA(+)], CD71(hi)) and mature (GYPA(+), CD71(neg)) erythroblasts confirmed the intramedullary loss of SS erythroblasts with progressive maturation. In patients with SCD, relative enrichment of donor erythroid precursors began to appear at the onset of hemoglobinization. Ineffective erythropoiesis of homozygous hemoglobin S (SS) progenitors thus provides a maturation advantage for homozygous hemoglobin A (AA) or heterozygous hemoglobin S/hemoglobin A (SA) donor erythroid precursor cells that results in greater donor contribution to overall erythropoiesis following stem-cell transplantation and improvement of clinical disease.

Adult↗