Mesenchymal Stem Cells Express the Surface Receptor Calreticulin (cC1qR) and Complement C1q Chemoattracts Them.
Bibliographic record
Abstract
Abstract Abstract 3855 Complement cleavage fragments play an important role in the trafficking of hematopoietic stem/progenitor cells as reported by us (Blood 2003;101:3784; Exp Hematol 2010;38:321; Transfusion Sept 2010), as well as of mesenchymal stem cells (MSC) as reported by others (J Immunol 2009;182:3827). Because MSC have a great potential for tissue regeneration and cellular therapies, in this study we investigated the mechanisms of migration of MSC to injured sites. As complement cascade is activated upon tissue injury we examined whether complement component 1 subcomponent q (C1q), the initiator of the classical pathway of complement activation, plays a role in the migration of MSC, and which C1q receptors (CR1, gC1qR, calreticulin (cC1qR), CD93) are expressed on MSC and could be involved in their migration. We previously reported that matrix metalloproteinases (MMPs), especially membrane type 1 (MT1)-MMP and MMP-2, regulate the migration of MSC (Stem Cells, 2006, 24:1254); therefore in this study we examined the effects of C1q on MMP expression and migration of MSC. Human MSC isolated from cord blood and bone marrow were maintained for 3–6 passages and characterized by adipocyte and osteoblast differentiation. We used chemoinvasion across the reconstituted basement membrane Matrigel to evaluate the migration of MSC, RT-PCR and flow cytometry to determine the expression of C1q receptors and, upon stimulation with C1q, zymography and Western blot to examine the expression of MMPs and ERK1/2 and PI3K/Akt signaling pathways. We found that MSC were chemoattracted by a C1q gradient in a dose-dependent manner, and MSC expressed transcripts for gC1qR, CD93 and cC1qR, but only calreticulin protein was detected on the surface of MSC. Specific antibody against calreticulin (anti-cC1qR antibody) inhibited the trans-Matrigel chemoinvasion of MSC towards C1q. Moreover, stimulation of MSC with C1q (10 μ g/mL) increased MT1-MMP expression, but no changes in MMP-2 secretion were observed. Trans-Matrigel migration of MSC towards C1q was also reduced by the MT1-MMP inhibitor EGCG. Further, the ERK1/2 inhibitor PD98059 and the PI3K inhibitor Ly294002 decreased the chemoinvasion of MSC towards C1q. In conclusion, this study indicates that: 1) C1q exerts chemoattractant activity towards MSC through its surface receptor calreticulin; 2) MT1-MMP regulates the C1q-induced trans-Matrigel migration of MSC; and 3) both the ERK1/2 and PI3K/Akt signaling pathways are involved in this process. These findings demonstrate a broader regulatory role for C1q, which functions as a chemotactic factor for MSC through its binding to surface calreticulin, and suggest a newly-found mechanism for the migration of MSC which may be important for its clinical use. Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".