The Past

Since the days of Aristotle, bone marrow has been used to augment the repair/regeneration of bone fractures or bone discontinuities (Connolly et al. 1989; Connolly 1998). The efficacy of bone marrow is, in part, due to the presence of osteoprogenitor cells, but also because of the presence of MSCs (Caplan 1991). As depicted in Fig. 1, generated as a working hypothesis in the late 1980s, MSCs can be separately induced into differentiation pathways, called lineages, which provide cells that separately produce bone, cartilage, muscle, tendon, ligament, fat, and bone marrow stroma (the connective tissue of bone marrow which physically and chemically supports hematopoiesis). In the late 1980s and early 1990s, the cells in bone marrow were separated and the MSCs purified. Culture expansion technologies were developed at that time to generate large quantities of MSCs that could be shown to be multipotent as depicted in Fig. 1 (Caplan 1989, 1991).

Fig. 1
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In the late 1980s, I proposed that bone marrow contained a multipotent mesenchymal progenitor which I called a “mesenchymal stem cell, MSC.” The figure depicts such a progenitor which can be induced into different lineage tracks to eventually contribute to bone, cartilage, etc. The style of this figure follows the logic of what was known at that time for the adult hematopoietic stem cell

Full size image

In strategies of tissue engineering, the MSCs, or lineage progressants, can be put into tissue-appropriate scaffolds in culture and matured into specific mesenchymal tissues. These in vitro managed composite constructs can then be surgically implanted into sites of tissue damage and tissue disease or left to “regenerate” the missing or afflicted tissue. A number of scaffolds and cell types have been used in this context, and several are now being used clinically in the orthopedic context (Caplan 1990; Young et al. 1998). That said, there are no scaffolds for cell loading approved in the USA. MACI and a collagen meniscus are available in Europe, but again, not in the USA.

The dramatic improvement of orthopedic surgical reconstructions with added bone marrow cannot be simply explained by the availability of osteogenic cells, so we began to explore other explanations for these positive findings. Moreover, our original clinical trials using MSCs were designed assuming that the MSCs home back to and resided in and differentiated into hematopoietic supporting marrow stroma (Lazarus et al. 1995). In cancer patients whose hematopoietic stem cells (HSCs) were ablated by chemotherapy or radiation, we hypothesized that subsequent bone marrow transplantations would be enhanced by adding marrow-derived culture-expanded MSCs that would “home back” to the stroma and enhance engraftment of donor HSCs. Indeed, MSCs administered directly before or after infusion of bone marrow were observed to enhance engraftment and more rapidly support hematopoietic replacement (Lazarus et al. 1995; Koc et al. 2000). In this case, it could be assumed that the MSCs, like other marrow stromal cells, secreted key regulatory molecules influential in both HSC engraftment and enhancing HSC lineage progressions into a variety of hematopoietic phenotypes.

The Present

Without reviewing all of the details for the current mode of action of exogenously added MSCs, it is quite clear that MSCs secrete massive amounts of bioactive factors which have two separate but overlapping functions: immunomodulation and trophic activity (Koc et al. 2000; Caplan and Correa 2011; Murphy et al. 2013). It is now well established that MSCs in marrow do not reside in the stroma but are found on blood vessels and sinusoids functioning in these locations as perivascular cells and pericytes (Caplan 2008; Crisan et al. 2008; Chen et al. 2013). Indeed, pericytes reside on EVERY blood vessel in the body. When these vessels are injured or inflamed, the pericytes come off and become MSCs that, depending on the anatomic site, secrete a number of site-specific growth factors and bioactive agents. These secreted bioactive agents from the front of the MSCs set up a curtain of molecules that immune cells cannot penetrate (Butler et al. 2008). For example, MSCs secrete molecules that drive down local levels of TNF-α and γ-INF, and in a prostaglandin-mediated process, huge amounts of IL-10 (Aggarwal and Pittenger 2005). This IL-10-rich microenvironment will stop the overaggressive immune system, especially interrogating T cells, from surveying the injured tissue. This powerful immune-regulatory activity is the body’s first line of defense against autoimmune reactions from becoming established. This curtain of molecules also protects infused allogeneic or xenogeneic MSCs from immediate detection from the host’s immune system. For example, a number of publications by us and others have shown that human MSCs are efficacious in rodent models of injury or disease (Bai et al. 2009; Bonfield et al. 2010; Wong 2011). The use of human MSCs in rodent disease or injury models represents, to me, a more logical preclinical model than using rodent autologous or syngeneic MSCs. Likewise, a number of investigators and corporations are using allogeneic MSCs in a diverse set of clinical trials ranging from graft-versus-host disease to Crohn’s disease, all of which involve a strong modulation of the host’s immune system (see ClinicalTrials.gov; search for mesenchymal stem cells).

In a separate secretary mode, the newly released and stimulated MSCs fabricate a spectrum of molecules that establish a tissue-regenerating milieu which we have been termed “trophic” (Dennis and Caplan 2004). This trophic activity involves four separate functions. First, molecules are produced that inhibit apoptosis due to ischemia caused by the breaking of the blood vessel. Second, MSCs inhibit the entrance and functioning of cells that fabricate scar. Third, the MSCs secrete large amounts of VEGF which brings in endothelial cells which form fragile, nascent blood vessels. The MSCs can then attach to these new blood vessels as pericytes and stabilize them. Last, the MSCs also secrete mitogens and other molecules that cause the tissue-specific stem cells to divide and differentiate into regenerated tissue to repair the local damage.

Clearly, these MSC secretory and regenerative functions have nothing to do with the multipotency of these mesenchymal stem cells (i.e., nothing to do with “stemness”). Thus, I propose to keep the MSC nomenclature but change the meaning to be “Medicinal Signaling Cells,” (MSCs) (Caplan 2010). Thus, MSCs are site-regulated, multidrug delivery vehicles, drug stores, that protect and organize the regeneration of injured or diseased tissues (Caplan and Correa 2011).

Over 400 clinical trials are listed on ClinicalTrials.gov when “mesenchymal stem cells” are used in that site’s search engine. A huge range of clinical conditions are being used with either autologous or allogeneic MSCs. All of these clinical situations involve either or both a need for immune modulation and/or tissue regeneration. Thus, the natural and intrinsic activities of donor MSCs derived from pericytes are being directed against the injury or inflammation site(s) of the host. Importantly, these intrinsic, powerful immunomodulatory, and trophic activities survive culture expansion, freeze-thawing, and the shock of reentering the patient’s bloodstream or damaged tissue.

The infused or implanted MSCs find broken or inflamed blood vessels and dock at these sites of injury or inflammation since this is where these cells naturally function. Clearly, only a few such MSCs are needed to affect a therapeutic outcome since they have a pronounced effect on the local tissue. Thus, I would suggest that MSCs help manage the host’s intrinsic regeneration capacity by adding to and intensifying the injured tissue’s innate capacity to regenerate itself. This occurs because MSCs sense this dysfunctional local environment and respond by secreting molecules that stimulate that site to fix itself.

The Future

Orthopedic Sports Medicine practitioners treat a large range of conditions. A ruptured ACL or Achilles tendon will not be regenerated by delivering MSCs into the injury site. That said, mild or severe tendonitis can be treated by injecting MSCs into the afflicted tissue. Thousands of horses with such tendonitis have been treated with a crude but purified preparation of autologous MSCs from the horses’ resected fat tissue (see www.vet-stem.com). Likewise, I would suggest that if the torn or ruptured Achilles tendon can be sutured back together, that subsequent exposure to MSCs during the repair process could, in principle, decrease the inflammation, decrease the scarring, and enhance the site-specific regeneration (not repair!) of the tendon tissue by mobilizing the cells intrinsic to the injured tissue.

For patients who have had partial meniscectomies or spinal disc dysfunction (and back pain), the injection of allogeneic, culture-expanded, frozen-thawed MSCs into the synovial joint or disc, respectively, has been reported to have quite positive clinical outcomes. Indeed, from MRI measurements, it seems clear that the host tissue, meniscus and disc, has increased in volume and the clinical conditions modified (Vangsness et al. 2014; see Mesoblast website, press release 1–2014). These clinical trials were based on positive observations of large animal models in goats and sheep using allogeneic MSCs (Murphy et al. 2003; Ghosh et al. 2012).

For emphasis, we must use these cell-based therapies after well-controlled clinical trials have been completed and sufficient evidence-based medical protocols have been approved by our hospitals and their IRBs. At Case Western Reserve University and University Hospitals Case Medical Center and at other institutions worldwide, phase I clinical trials that are investigator initiated will be useful to set the procedures and perfect these cell-based therapies. Given successful phase I trials and proven safety of these cell-based therapies, I have put forth a suggested accelerated regulatory pathway to bring such therapies more rapidly to the patients who need them (Caplan and West 2014). This accelerated pathway would be quite useful for Orthopedic Sports Medicine since the management of young patients’ intrinsic regenerative capacity would seem to be easier than that for geriatric patients.

The introduction of new clinical protocols into standard medical practice will require that practitioners take a more active role in the initiation of new procedures and reagents in the absence of commercial influence. In orthopedics, it is the practitioners who are best suited to develop new, innovative protocols since they best understand the range and diversity of clinical situations. Cell-based therapies hold the potential for assisting afflicted tissue to regenerate. The timing and placement of cells into the damage tissue sites in both the acute and chronic conditions will require new expertise and experience within the clinical settings. Practitioners hold the special responsibility to their individual patients to provide “best practice”-based care, and they should be responsible for developing the best protocols. Just as the modern use of whole bone marrow for orthopedic bone repair surgeries was developed by the orthopedic surgeons themselves (Connolly et al. 1989; Connolly 1998), so should cell-based therapies be refined by practitioners. Indeed, the image of the orthopedic surgeon as a carpenter who uses hammers, screws, and nails to repair body parts will, in time, change to be the image of the orthopedic cell therapist and tissue engineer of mesenchymal tissues.

The new era of cell therapies is now emerging, and their future use will change the way orthopedics is practiced and put new demands upon the practitioner. This new era does not change the role of the orthopedic practitioner because they have always been the orchestrator who helps to manage the body’s intrinsic repair and regeneration capacity. The new era will require new skills and will use new tools to manage and orchestrate the body’s repair and regeneration capacity. The orthopedic practitioner will be retitled as the cell biologist and tissue engineer. Thus, the future for Orthopedic Sports Medicine will be enhanced by new, more long-term successful and new skill sets and medical options.