Introducing HSC Dosing to Hematopoietic Stem Cell Transplantation Medicine
At the end of 2015, James Sherley, director of stem cell medicine biotechnology company Asymmetrex, listed 9 areas of stem cell medicine that could improve in 2016, if new methods for counting tissue stem cells were employed. Hematopoietic stem cell transplantation (HSCT) medicine headed the list
The most established stem cell medical treatment is hematopoietic stem cell transplantation (HSCT) therapy. HSCs are adult tissue stem cells found naturally primarily in the bone marrow and in umbilical cord blood. In addition, medical treatments called mobilizations can induce the cells to move from the bone marrow into the blood stream. HSCs function to initiate and sustain production of the many different mature blood cells, including red blood cells, white blood cells, and platelets, that must be continuously replenished throughout life.
Each year, worldwide, as many as 50,000 HSCTs are performed to restore normal, mature, blood cell production disrupted by diseases or medical treatments that injured, transformed, or destroyed patients’ HSCs (Gratwohl et al. 2010). By far, the major need for HSCT is to restore HSCs destroyed by high dose chemotherapy treatments designed to eradicate cancers (Gratwohl et al. 2010; emedicine/#a4).
As a well-established medical procedure available primarily in major medical centers in developed countries, HSCT is highly effective (Gratwohl and Baldomero, 2009; Gratwohl et al. 2010). Although patients receiving HSCT may still succumb to their underlying illness at high rates (emedicine/#a4), the procedure itself is quite robust. Because HSCT is performed either to correct an intrinsic defect in primary hematopoiesis or to reconstitute hematopoiesis ablated to treat autoimmune illnesses (e.g., multiple sclerosis), a partial defect in blood formation (e.g., sickle cell disease), or cancers, it can be difficult to determine how often HSCT itself fails (Wolff, 2002; Olsson et al. 2013). Patient survival in each treatment setting is dependent on many other factors besides the efficiency of establishing a good HSC transplant graft that restores effective hematopoiesis.
Recognizing this challenge to estimating rates of HSCT graft failure, the current best estimate is about 5% overall, based in part on the need for second and even third transplants in treated patients (Wolff, 2002). In some special patient populations, this rate can be higher, e.g., patients receiving umbilical cord blood transplants as a source of HSCs (18–24%; Olsson et al. 2013) or patients receiving HSCT from matched unrelated donors (10–15%; emedicine/#a5). However, these must be viewed as conservative estimates because of confounding by effects of many other treatment factors and disease progression (Wolff, 2002; Olsson et al. 2013). In any case, graft failure is a significant cause of patient morbidity and mortality, impacting thousands of HSCT patients worldwide each year.
One leading cause of graft failure is insufficient number of transplanted HSCs (Wolff, 2002; Olsson et al. 2013). However, surprisingly, HSCT continues to be practiced around the world without the benefit of knowing the dose of HSCs transplanted. To get a full sense of the starkness of this paradox, consider the following results for the number of articles identified in PubMed searches for the following terms (Table 1).
Table 1. PubMed articles identified for the indicated HSCT-related search phrases.
Number of articles
“HSCT” + “hematopoietic stem cell transplant/ation”
“HSCT dose” + “hematopoietic stem cell transplant/ation dose”
“HSC dose” + “hematopoietic stem cell dose”
“TNC dose” + “total nucleated cell dose”
“CD34 dose” + “CD34 cell dose”
So, amazingly, although the dose of transplanted HSCs is one of the most important factors for success in HSCT, this metric is barely mentioned in tens of thousands of reports on HSCT biomedical research that span nearly a half-century. Why? Because there has been no means to accurately quantify human HSCs.
The contrastingly small number of biomedical reports that include the terms “HSCT dose” or “HSC dose” also indicates very little active research to address this problem. That is the current stagnant state of affairs. Although significant improvements in HSCT medicine with benefits to patients could be had with HSC dosing information, this important area of clinical practice has become resigned to making measurements that actually provide no reliable information about HSC dose.
The technical and conceptual resignation has been to use CD34-positive cell count and/or TNC count as surrogates for an unavailable HSC cell count (Wolff, 2002; Olsson et al. 2013; Bai et al. 2014; Rich, 2015). Standardized minimal levels for CD34 cell and TNC counts have been established to keep graft failure rates in the range of 1–5%, even with cord blood HSCT (Rich, 2015). However, even these failures might be prevented if HSC dose were known; and in any individual case, CD34 cell or TNC counts may not be prognostic, because they are aggregate indicators of HSC number, but are neither exact nor precise. TNC count lacks any reliable correlation with HSC number; and the HSC biomarker, CD34, is not expressed on all HSCs, while also being expressed on committed progenitor cells that outnumber HSCs in most transplant preparation by >10,000:1. Other assays like colony-forming units (CFU) also lack sufficient specificity to quantify HSCs (Rich, 2015).
Among the proposed “9 Ways Stem Cell Biology and Stem Cell Biomedicine Would Improve in 2016, If New Stem Cell Counting Technologies Were Deployed” (http://asymmetrex.com/9-Improvements-We-Could-See-in-2016-Thanks-to-Biotechnology), items 1–4 addressed the impact of being able to determine HSC dose for HSCT medicine
- The dose of tissue stem cells in approved cell therapy treatments would be known for the first time. These include blood stem cells found in bone marrow and umbilical cord blood.
- Patients would no longer be treated with tissue cell preparations that have too few stem cells, leading to tragic outcomes.
- Patients would no longer be treated with tissue cell preparations that have more stem cells than needed, wasting the valuable cells.
- Samples in public cord blood banks could be stratified to insure that larger children received samples with higher numbers of blood stem cells as is required.
As a further point to emphasize for the predicted impact of technologies for counting HSCs, consider the Stem Cell Therapeutic and Research Act of 2005. This legislation was enacted in the U.S. to provide patients receiving cord blood HSCT with better protection for safe and efficacious treatments. The Act requires that donor cord blood units have “high quality and potency.” However, currently, the essential basis for meeting these criteria is TNC and volume (Rich, 2015)! Again, there is no mention of the most crucial therapeutic factor, HSC number, because it has not been available.
Asymmetrex’s new AlphaSTEM technology for counting adult tissue stem cells has the capability of determining HSC number reliably in transplant preparations. Developed in collaboration with computer simulation partner AlphaSTAR Corporation, the new technology provides robust data for HSC number, viability, and stem cell function. Among its many applications, Asymmetrex is working to provide this service immediately to cord blood banks and HSCT transplant centers worldwide. For those interested, a slide deck with details of the technology can be found at (http://asymmetrex.com/our-products/drug-development-regenerative-medicine).
- Bai, L et al. (2014) Factors predicting haematopoietic recovery in patients undergoing autologous transplantation: 11‑year experience from a single centre. Ann Hematol 93, 1655–1664.
- Ballen, K. K., Gluckman, E., and Broxmeyer, H. E. (2013) Umbilical cord blood transplantation: the first 25 years and beyond. Blood 122, 491–498.
- Gratwohl, A et al. (2010) Hematopoietic stem cell transplantation: A global perspective. JAMA 303, 1617–1624.
- Gratwohl A. and Baldomero, H. (2009) Trends of hematopoietic stem cell transplantation in the third millennium. Curr Opin Hematol 16, 420–426.
- McKenna, D. and Sheth, J. (2011) Umbilical cord blood: Current status & promise for the future. Indian J Med Res 134, 261–269
- Olsson, R et al. (2013) Graft failure in the modern era of allogeneic hematopoietic SCT. BMT 48, 537–543.
- Rich, I.N. (2015) Improving quality and potency testing for umbilical cord blood: A new perspective. SCTM 4, 967–973.
- Wolff, S. N. (2002) Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection, or relapse after allogeneic transplantation. BMT 29, 545–552.
Interested in learning more? Check out the free webinar on counting adult tissue stem cells for applications in regenerative medicine and drug development.