The debate about hematopoietic stem cell numbers and productive capacity is relevant to many areas of clinical and experimental hematology. Recently, Abkowitz et al1 reported that the total number of stem cells in mammals is conserved so that mice, cats, humans, and possibly elephants have the same-sized stem cell pools. They emphasized that, since humans live longer than mice and need to produce more blood cells, human stem cells must be capable of producing many more blood cells than murine stem cells. A corollary of this is that the frequency of stem cells in human bone marrow will be lower than the frequency in murine bone marrow. Since we have made similar measurements in mice and calculations in humans,2,3 we were interested in determining whether our data are consistent with those of Abkowitz et al1 and whether the calculated numbers of stem cells in humans can account for the daily requirement to replace mature blood cells lost through senescence.

Table 1 compares earlier data, obtained using 59Fe ferrokinetics to estimate marrow cellularity and the spleen colony (CFU-S) assay4 to measure hematopoietic stem cells in 3 strains of mice,2 with the values reported by Abkowitz et al.1 Our data indicate slightly greater values than Abkowitz et al,1 but they are of the same order of magnitude. Table 1 also shows data for the derived frequency of human hematopoietic stem cells, assuming that the human hematopoietic stem cell population is the same size as that of the mouse, which again is consistent with that reported by Abkowitz et al.1 

Table 1.

Numbers and frequencies of hematopoietic stem cells (HSCs)

 Number Frequency of HSCs 
Mice   
 Abkowitz et al1 11 200-22 400 HSCs/mouse* 4-8 HSCs/105 BM cells  
 Coggle et al2 36 000-125 000 HSCs/mouse 7-14 HSCs/105 BM cells 
Humans   
 Abkowitz et al1 11 200-22 400 HSCs/person 0.7-1.5 HSCs/108 BM cells 
  (mean)  (16 800 HSCs/person)  
 Gordon et al3 36 000-125 000 HSCs/person 2.4-8.3 HSCs/108 BM cells 
  (mean)  (81 000 HSCs/person)  
Elephants8   
 Abkowitz et al1 11 200-22 400 HSCs/elephant 0.8-1.5 HSCs/1010 BM cells 
  (Mean)  (16 800 HSCs/elephant)  
 Gordon et al3
 
36 000-125 000 HSCs/elephant 2.4-8.3 HSCs/1010 BM cells1-153 
  (Mean)  (81 000 HSCs/elephant)  
 Number Frequency of HSCs 
Mice   
 Abkowitz et al1 11 200-22 400 HSCs/mouse* 4-8 HSCs/105 BM cells  
 Coggle et al2 36 000-125 000 HSCs/mouse 7-14 HSCs/105 BM cells 
Humans   
 Abkowitz et al1 11 200-22 400 HSCs/person 0.7-1.5 HSCs/108 BM cells 
  (mean)  (16 800 HSCs/person)  
 Gordon et al3 36 000-125 000 HSCs/person 2.4-8.3 HSCs/108 BM cells 
  (mean)  (81 000 HSCs/person)  
Elephants8   
 Abkowitz et al1 11 200-22 400 HSCs/elephant 0.8-1.5 HSCs/1010 BM cells 
  (Mean)  (16 800 HSCs/elephant)  
 Gordon et al3
 
36 000-125 000 HSCs/elephant 2.4-8.3 HSCs/1010 BM cells1-153 
  (Mean)  (81 000 HSCs/elephant)  
*

Calculated from frequency by × 2.8 × 108 BM cells/mouse.

Calculated from frequency by × 5-9 × 108 BM cells/mouse.

Calculated from number by ÷ 1.5 × 1012 BM cells/person.

F1-153

Calculated from number by ÷ 1.5 × 1014 BM cells per elephant, under assumption that elephants have the same number of stem cells as mice and humans. See Table 2.

Adult humans need to produce 1 × 1011 neutrophils and 2 × 1011 red blood cells per day throughout life. Assuming a lifespan of 80 years, this amounts to a total of 80 × 365 × 3 × 1011 (8.8 × 1015) for these 2 lineages alone, which must be generated by 16 800 (Abkowitz et al1) or 81 000 (our data) stem cells. Assuming steady-state stem cell kinetics5 and 100 stem cell replications per lifetime, stem cell division and self-renewal with a probability of 0.5 will result in 1.68 × 106 to 8.1 × 106 new stem cells available for differentiation and, ultimately, mature blood cell formation. Consequently, each of these stem cells must be responsible for producing 1.1 × 109 to 5.2 × 109mature cells. It is noteworthy therefore that Brummendorf et al6 reported that single stem cells generate, on average, nearly 109 CD34+CD38 cells in vitro and the greatest number observed was more than 1012. The corresponding stem cell frequency would be 1 in 5 × 108 to 10 × 108. As noted by Abkowitz et al,1 these frequencies are much lower than the frequencies of candidate human stem cells measured in the NOD/SCID transplantation model.7 Clearly, if stem cells did not self-renew, they would need to be capable of producing many more cells to sustain hematopoietic cell production throughout life. If this were the case, each of the 16 800 to 81 000 stem cells would be required to produce on average 1.1 × 1011 to 5.2 × 1011 mature cells and their frequencies would be commensurately 2 orders of magnitude lower. Moreover, at such low frequencies a total marrow cellularity of 1.5 × 1012could accommodate only a very few stem cells.

Insufficient data are available to estimate the size of the stem cell pool and kinetic parameters in elephants accurately (Table 2). But simple calculations of the possible frequency and productive capacity of elephantine stem cells can be made. The data in Table 1 and Abkowitz et al1 indicate that mice, cats, and humans have on the order of 1 × 1010 to 2 × 1010bone marrow cells per kilogram of body weight. If the same is true of elephants, a large African elephant of 7 500 kg (Table 2) could have as many as 1.5 × 1014 bone marrow cells. The corresponding frequencies of stem cells in such animals would be 1 to 8 per 1010 if all species have the same number.1Furthermore, elephants have many more blood cells than mice or humans (Table 1), up to 10 × 1012. If red and white cell kinetics are similar in humans and elephants, who live about the same length of time, a large African elephant will need to produce 17.5 × 1020 cells in a lifetime. This number corresponds to 2 × 1014 to 10 × 1014 cells per stem cell.

Table 2.

Asian and African elephant characteristics

 Asian African  
Body weight, kg 3000-4000 6000-7500  
Blood volume, L 300-400 600-750  
White cell count, × 109/L 9.8-25.3 4.4-12.8  
Total white cells per elephant, × 1012 2.9-10.1 2.6-9.6 
 Asian African  
Body weight, kg 3000-4000 6000-7500  
Blood volume, L 300-400 600-750  
White cell count, × 109/L 9.8-25.3 4.4-12.8  
Total white cells per elephant, × 1012 2.9-10.1 2.6-9.6 

Zoological Society of London, personal communication, August 2002.

In summary, the experimental and theoretical estimates of stem cell pool size in humans are not inconsistent with lifelong requirements for blood cell production sustained by a self-renewing stem cell population. Nor do the values we have derived appear to be inconsistent with the idea that mice, cats, humans, and elephants could have similar numbers of stem cells.1 

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