 Haematopoietic stem cells (HSCs) are the “seeds” of the cells that constitute our blood and immune system. In adult humans, the home of these progenitor cells is the bone marrow, a complex soft tissue that occupies hollow spaces inside bones, particularly large, flat bones.
Throughout the span of our life, a large number of HSCs continuously differentiate in order to fill up the blood and lymphoid organs with mature cells and replace the cells that reach the end of their useful life or are otherwise eliminated or lost. Thus, HSCs are essential for our development and survival. In addition, HSCs’ ability to repopulate the blood and immune system is an extremely useful property to treat certain disorders. In fact, infusion of HSCs can “rescue” the subject from a failure of the bone marrow that may result from marrow disorders or exposure to radiation therapy or chemotherapy, by generating a progeny of new healthy cells. In experiments, a single HSC has repopulated the blood of a mouse that received an otherwise lethal dose of nuclear radiation!
HSCs in the clinic: haematopoietic stemcell transplantation
Today, haematologists routinely utilise HSC infusion in a procedure called haematopoietic stem cell transplantation (HSCT) to promote the recovery of blood cell numbers in people who received high doses of immunosuppressive radiation therapy or chemotherapy. Normally, HSCs are obtained either by direct aspiration of the bone marrow from the hip bones or through mobilisation of the progenitor cells into the peripheral blood. Administration of a blood cell growth factor that stimulates production and the release of stem cells induces HSCs to move out of the bone marrow and into the bloodstream.
Blood is drawn from the patient into a cell separator machine, which collects the mobilised HSCs together with white cells in a process called leukapheresis. HSCs can subsequently be purified by selecting cells bearing the marker CD34, which they specifically express on the cell membrane. Umbilical cord blood is also rich in HSCs and has been utilised for haematopoietic transplants for cancer, particularly in children who did not have a matching bone marrow donor. The HSCs can be obtained from the same patient and preserved for re-infusion after the chemotherapy; this procedure is named autologous haematopoietic stem cell transplantation (Fig. 1). Alternatively, a genetically “matching” donor can be identified among the person’s relatives or through a bone marrow or cord blood donors’ registry; the transplantation of HSCs from another individual is termed allogeneic transplantation. Allogeneic and autologous HSCT have different indications and both are used extensively for treating cancers of the blood, of the lymphoid organs and of the bone marrow. Indeed, transplantation of HSCs has been a life-saving treatment for tens of thousands of people affected by leukaemia, lymphoma, myeloma and other malignancies.
 HCST for “immune repair”
Clinical studies investigating the potential usefulness of HSCT in MS and other immunemediated disorders were initiated, following the observation of those people with an autoimmune disease who, after developing cancer, were treated with HSCT and experienced a remission of the autoimmune disorder. These trials have been limited to autologous HSCT since allogeneic transplantation has a higher risk of side-effects and serious complications.
How does autologous HSCT work in MS?
The lesions in MS are infiltrated by bloodoriginating immune cells including T and B lymphocytes that seem to attack and injure myelin-producing cells. We do not know what causes this attack but the process almost certainly involves a dysfunction of the immune system. The goal of HSCT in MS is to purge the existing immune system with immunosuppressive chemotherapy and regenerate a pool of new and healthy immune cells originating from HSCs. The idea has been ingeniously termed as the “resetting of the immunological clock”. This means that in principle the mature cells of the immune system, and amongst them the cells that attack the brain, can be eliminated and replaced by new, harmless cells. Recent studies have proven that this “resetting” of the immune system actually occurs and that the thymus, the organ where haematopoietic progenitor cells mature into T lymphocytes, is reactivated after HSCT giving rise to large numbers of new T cells, possibly including “regulatory” T cells that suppress autoimmune attacks.
What can HSCT do for people with MS?
At the time of writing, more than 350 people with MS have undergone autologous haematopoietic stem cell transplantation.
Although no randomised controlled studies rigorously assessing the efficacy have yet been completed, an analysis of the reported results provides some indication on what this treatment can and cannot do at the present time. Firstly, HSCT generally has shown beneficial suppressive effects on inflammation and development of new plaques as detected by MRI. In the overall majority of treated individuals there was a stabilisation of the preexisting neurological disability. Although in principle HSCs can transform into any cell lineage, including neural or myelin-producing cells, we do not know whether HSCs can directly help repair the neural structures that have already been damaged by MS. The clinical studies found that those who had a higher and chronically established degree of disability prior to HSCT frequently continued to worsen posttherapy.
This observation suggests that those individuals suffered from a type or stage of neural deterioration that was not (or no longer) caused by the typical inflammation that HSCT could not reverse or even arrest, in spite of its powerful effects on the immune system.
Therefore, clinical trials are now seeking to recruit earlier in the disease course, patients with very active forms of MS who failed to respond to other immune treatments, in order to determine if HSCT can prevent them from worsening.
Current difficulties and hope through research
The main difficulty in clinical studies of HSCT for MS is the issue of treatment-related risks. Fatal complications have resulted from HSCT and while these occurrences have been decreasing owing to improved knowledge and technology, life-threatening side-effects can still occur. Another challenge is identifying early those who are affected by a severe form of MS and fail to respond to other treatments. It can be reasonable to consider the option of an intensive therapeutic intervention for these people, such as “immune repair” through HSCT.
Treatment with HSCT should preferably be received through participation in a qualified clinical trial. Studies combining clinical and laboratory research can help make HSCT safer and more effective and can teach us how changes in the immune system can control the development and course of MS.
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